1,4-substituted piperidine derivatives

ABSTRACT

Described herein are 1,4-substituted piperidine compounds according to Formula I that have demonstrated activity as fatty acid synthase inhibitors. Also described herein are pharmaceutical compositions containing the described 1,4-substituted piperidine compounds, and methods of treating diseases mediated by fatty acid synthase, by administering one or more of the compounds or pharmaceutical formulations described herein. Also described herein are methods of synthesizing the compounds described, including the described 1,4-substituted piperidine compounds and synthetic intermediates useful in those syntheses

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/185,710, filed on Jun. 17, 2016, which claims the benefit of U.S.provisional patent application No. 62/181,384, filed Jun. 18, 2015, eachof which is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds according to Formula I, aswell as to pharmaceutical compositions containing these compounds and tomethods of treatment of cancer, and to methods of treatment of weightgain associated with antipsychotic drug therapy, the methods comprisingadministering a therapeutically effective dose of one or more of thecompounds of Formula I, or a pharmaceutical composition comprising oneor more of the compounds of Formula I, to a patient in need of suchtherapy

BACKGROUND

Fatty acid synthase (FASN) is a multi-enzyme protein complex thatcatalyzes the synthesis of fatty acids involved in energy production andstorage, cellular structure and formation of intermediates in thebiosynthesis of hormones and other biologically significant molecules(Nature Reviews Cancer, 2007, 7, 763-777). FASN is composed of twoidentical 272 kDa multifunctional polypeptides. As its main function, itcatalyzes the synthesis of palmitate from acetyl-CoA and malonyl-CoA, inthe presence of nicotinamide adenine dinucleotide phosphate (NADPH). Innormal human tissues (with the exception of liver and adipose tissue),fatty acids are preferentially acquired from the diet, and expression ofFASN levels are low. In contrast, FASN expression and activity is highlyelevated in several pathological states including cancer, inflammatoryand metabolic diseases. In particular, evidence shows that increasedendogenous fatty acid synthesis is critical for tumorigenesis.

Cancer is a disease of accelerated cell growth and proliferation. Cancercells adapt metabolically to increase levels of lipids to support theiranabolic requirements. Increased synthesis of fatty acids represents afundamental metabolic adaptation of cancer cells and is facilitated byhigh levels of FASN expression. Increased expression of FASN is an earlyevent in tumorigenesis and is found in numerous tumor types, oftencorrelating with a poor prognosis (Nature Reviews Cancer, 2007, 7,763-777). FASN gene amplification and protein overexpression wasobserved in human breast, ovarian, prostate, colon, lung, bladder,stomach and kidney cancers suggesting FASN as a potential drug targetand marker of poor prognosis (Nature Reviews Cancer, 2007, 7, 763-777;Anticancer Res. 2007, 27, 27-34; Cancer Res., 2006, 66, 5977-5980,Nutrition, 2000, 16, 202-208).

In addition to tumor cells, immune cells metabolically adapt,proliferate and differentiate into distinct functional classes inresponse to immunogenic stimuli. Studies have demonstrated thatlipogenesis plays a critical role in immune responses and metabolicadaptation of activated immune cells. Inhibition of fatty acid synthesisduring T-cell differentiation result in a switch from Th17 to Tregcells, suggesting a novel approach to treat autoimmune diseases, such asmultiple sclerosis, and to modulate immune responses (Nature Medicine,2014, 20, 1327-1333). Similarly, de novo fatty acid synthesis iscritical for CD8+T cell expansion and dendritic cell activation (NatureImmunology, 2014, 15, 323-332). These results demonstrate thatmodulation of the fatty acid synthesis pathway might represent astrategy to control immune responses and to treat a wide range ofautoimmune diseases.

FASN has been implicated as an important enzyme promoting a life cycleof multiple viruses and microorganisms. De novo lipid biosynthesis hasbeen shown to be necessary for replication of the Flaviviridae familyincluding Hepatitis C Virus, Dengue virus, yellow fever virus, West Nilevirus and others (Chemistry and Biology, 2013, 570-582). Inhibition ofFASN by small molecule inhibitors such as Cerulenin and Orlistatresulted in a strong inhibition of viral replication. Other viruses alsodepend on FASN activity including human cytomegalo virus (HCMV)influenza A, Epstein-Barr virus (EBV) and coxsackievirus B3 (CVB3).Numerous genome wide screens identified multiple host genes involved inlipid metabolism which are crucial for replication of viruses andincreased expression FASN is often required for efficient viralreplication (Nature Biotechnology, 2008, 26, 179-186). Taken together,these results provide a strong rationale for targeting FASN for theantiviral therapy.

Fatty acid accumulation is associated with variety of metabolic diseasesand has been shown to contribute to their pathogenesis. Thenon-alcoholic hepatic steatosis (NASH), also called fatty liver disease,encompasses a spectrum of liver diseases (steatosis, steatosis withinflammation, cirrhosis) characterized by a fatty acid accumulation inhepatocytes. Currently, NASH is the most common liver disease indeveloped countries and is associated with obesity, insulin resistanceand type 2 diabetes. Studies in animal models demonstrated thatpharmacological inhibition of FASN improved hepatic function anddecreased liver fat accumulation (PloS One, 2013, 9, 1-8).

FASN is highly expressed in tissues with high metabolic activity (liver,adipose tissue and brain), and is a critical enzyme for endogenouslipogenesis and modulation of key intermediates of lipid andcarbohydrate cellular metabolism. A FASN inhibitor has been proposed fortreatment of obesity, and inhibition of FASN in the hypothalamus mayresult in reduced food intake. The non-specific irreversible FASNinhibitors cerulenin and C-75 have been reported to decrease brainlevels of orexigenic neuropeptides and decrease food intake. Therefore,FASN inhibition represents a therapeutic target in a wide spectrum ofpathologies including cancer, antiviral, liver and cardiovasculardiseases and treatment of obesity, diabetes and drug-induced body weightgain; e.g. antipsychotics.

Recent advances in the treatment and management of cancer show that manyanticancer therapies lead to profound changes in tumor metabolism.Inhibition of BRAF signaling by vemurafenib and inhibition of BCR-ABL byimatinib led to increased oxidative phosphorylation (Pollak M, (2013)Targeting Oxidative Phosphorylation: Why, When and How; Cancer Cell 18,263-63). Such a drug-induced reprogramming of cellular metabolism fromglycolysis to oxidative phosphorylation might create a dependency onlipids which could be exploited therapeutically by use of FASNinhibitors. In yet another example, it was demonstrated that cessationof the anti-angiogenic therapy by sunitinib and sorafenib resulted in arapid regrowth of tumors and increased metastasis which were mediated bya rapid metabolic switch of tumor and stromal cells to de novolipogenesis. Pharmacological inhibition of FASN was sufficient toreverse tumor regrowth and metastatic dissemination further confirmingthe role of lipid metabolism in tumor adaptation to anticancer therapies(Sounni N E, Cimino J, Blacher S, Primac I, Truong A, Mazucchelli G,Paye A, calligaris D, Debois D, mari B, de pauw E, Noel A (2014)Blocking Lipid Synthesis Overcomes Tumor Regrowth and Metastasis afterAngiogenic Therapy Withdrawal; Cell Metabolism 20, 1-15) and providing arationale for combinatorial treatments using FASN inhibitors.

SUMMARY

This application relates to compounds according to Formula I:

including all stereoisomeric forms, and mixtures of stereoisomeric formsof these compounds. The application further relates to salts ofcompounds according to Formula I, e.g., pharmaceutically acceptablesalts, and to compositions, e.g., pharmaceutical compositions, thatcontain compounds according to Formula I, or salts thereof.

The compounds of Formula I and/or their pharmaceutically acceptablesalts are useful for treating conditions, disorders and diseases thatare directed or indirectly controlled, mediated, affected or influencedby FASN expression. Compounds of Formula I are FASN inhibitors and aretherefore useful in the treatment of various conditions, disorders ordiseases mediated by FASN expression, including conditions related tocancer, metabolic disorders, and the central nervous system (CNS).

DETAILED DESCRIPTION

The following provides additional non-limiting details of the compoundsof Formula I, as well as various species and more specific embodimentsof the same, intermediates, and synthesis processes.

One aspect of this application is directed to compounds of Formula I:

and salts thereof, e.g., pharmaceutically acceptable salts thereof,wherein:

A is selected from —C(═O)— and —SO₂—;

R¹ is selected from —H, —(C₁-C₁₀) hydrocarbyl, substituted —(C₁-C₁₀)hydrocarbyl, 3-7 membered heterocyclyl, substituted 3-7 memberedheterocyclyl, —(C₆-C₁₀) aryl, substituted —(C₆-C₁₀) aryl, 5-6 memberedheteroaryl, substituted 5-6 membered heteroaryl, —NR⁷R⁸, —OR⁷, —SR⁷,—N(OR⁸)R⁷, —N(SR⁸)R⁷ and —C(═O)—(C₁-C₆) alkyl;

a and b are independently selected from 0 and 1;

each R² is independently selected from —H and —(C₁-C₄) alkyl;

each R³ is independently selected from —H and —(C₁-C₄) alkyl

R⁴ is selected from —H, —(C₁-C₆) alkyl, ═O, —OH, —O(C₁-C₆) alkyl,halogen, and —CN; wherein one of the R³ groups can optionally bestructurally connected to one of the R² groups to form an alkylenebridge to produce a bicyclic ring; or

one of the R³ groups can optionally be structurally connected to the R¹group to form a 5 to 7 membered heterocyclyl ring fused to the 1-2 faceof the piperidine ring; or

one of the R³ groups can optionally be structurally connected to the R⁴group to form a 5-7 membered carbocyclic or heterocyclic ring fused tothe 2-3 face of the piperidine ring;

indicates that the designated bond is a carbon-carbon single bond or acarbon-carbon double bond;

X is selected from —O—, —S—, —SO—, —SO₂—, —NH— and —NR⁹—;

W¹, W² and W³ are independently selected from N, CH, and C—R¹⁰; providedthat W² and W³ are not both N;

R⁵ is selected from —H, —C₁-C₇ hydrocarbyl, —C₃-C₆ heterocyclyl;halogen, —(C₁-C₃) haloalkyl, —OR^(7a), —CN, —NR^(7a)R^(8a),—O(CH₂)_(n)NR^(7a)R^(8a), —O(CH₂)_(n)OR^(8a),—NR^(8a)(CH₂)_(n)NR^(7a)R^(8a), —NR^(8a)(CH₂)_(n)OR^(8a),—C(═O)NR^(7a)R^(8a), —C(═O)OR^(7a), 5-6 membered heteroaryl, substituted5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, andsubstituted 8-10 membered bicyclic heteroaryl;

n is an integer selected from 1, 2, 3, and 4;

R⁶ is selected from 6-membered heteroaryl, substituted 6-memberedheteroaryl, 9-10 membered bicyclic heteroaryl, and substituted 9-10membered bicyclic heteroaryl;

R⁷ is selected from —H, —(C₁-C₇) hydrocarbyl, substituted —(C₁-C₇)hydrocarbyl, —C(═O)R⁸, —(C₁-C₆) heteroalkyl, 6 membered aryl, 5-6membered heteroaryl and 5-6 membered heterocyclyl;

R⁸ is selected from —H, and —(C₁-C₆) alkyl, wherein R⁷ can optionally bestructurally connected to R⁸ to form a 5 to 7 membered heterocyclylring;

R^(7a) is selected from —H, —(C₁-C₇) hydrocarbyl, substituted —(C₁-C₇)hydrocarbyl, —C(═O)R⁸, and —(C₁-C₆) heteroalkyl;

R^(8a) is selected from —H, and —(C₁-C₆) alkyl, wherein R^(7a) canoptionally be structurally connected to R^(8a) to form a 5 to 7 memberedheterocyclyl ring;

R⁹ is selected from —(C₁-C₇) hydrocarbyl, wherein R⁹ can optionally bestructurally connected to R⁴ to form a 5 to 7 membered heterocyclylring;

each R¹⁰ is independently selected from —(C₁-C₇) hydrocarbyl,substituted —(C₁-C₇) hydrocarbyl, halogen, —C(═O)(C₁-C₇) hydrocarbyl,—C(═O)NH₂, —C(═O)NH(C₁-C₇) hydrocarbyl, —C(═O)N(C₁-C₇)hydrocarbyl)₂,—OH, —O(C₁-C₇) hydrocarbyl, substituted —O(C₁-C₇) hydrocarbyl, —(C₃-C₆)heterocyclyl, substituted —(C₃-C₆)heterocyclyl —CN, —NH₂,—NH(C₁-C₆)alkyl, —N(C₁-C₆ alkyl)₂, —NH(CH₂)_(m)—R¹¹, —N(C₁-C₆alkyl)(CH₂)_(m)—R¹¹, —O—(CH₂)_(m)—R¹¹, and —(C₁-C₆) heteroalkyl;

m is an integer independently selected from 1, 2, 3, and 4; and

R¹¹ is selected from —O(C₁-C₆)alkyl, —N(C₁-C₆ alkyl)₂,—(C₃-C₆)heterocyclyl and substituted —(C₃-C₆) heterocyclyl.

According to some embodiments, A is —C(═O)—.

According to some embodiments, R¹ is selected from —H, —(C₁-C₁₀)hydrocarbyl, substituted —(C₁-C₁₀) hydrocarbyl, 3-7 memberedheterocyclyl, substituted 3-7 membered heterocyclyl, —(C₆-C₁₀) aryl,substituted —(C₆-C₁₀) aryl, 5-6 membered heteroaryl, substituted 5-6membered heteroaryl, —NR⁷R⁸, —OR⁷, —N(OR⁸)R⁷ and —C(═O)—(C₁-C₆) alkyl.

According to some embodiments, R¹ is selected from —(C₁-C₁₀)hydrocarbyl, substituted —(C₁-C₁₀) hydrocarbyl, 3-7 memberedheterocyclyl, substituted 3-7 membered heterocyclyl, —(C₆-C₁₀) aryl,substituted —(C₆-C₁₀) aryl, 5-6 membered heteroaryl, substituted 5-6membered heteroaryl, —SR⁷, —NR⁷R⁸, —N(OR⁸)R⁷, —N(SR⁸)R⁷ and—C(═O)—(C₁-C₆) alkyl.

According to some embodiments, R¹ is selected from —(C₁-C₁₀)hydrocarbyl, substituted —(C₁-C₁₀) hydrocarbyl, 3-7 memberedheterocyclyl, substituted 3-7 membered heterocyclyl, —(C₆-C₁₀) aryl,substituted —(C₆-C₁₀) aryl, 5-6 membered heteroaryl, substituted 5-6membered heteroaryl, —NR⁷R⁸, —N(OR⁸)R⁷ and —C(═O)—(C₁-C₆) alkyl.

According to some embodiments, R¹ is selected from —(C₁-C₆) alkyl,substituted —(C₁-C₆) alkyl, —(C₃-C₆) cycloalkyl, substituted—(C₃-C₆)cycloalkyl, —(C₂-C₆) alkenyl, substituted —(C₂-C₆)alkenyl,benzyl, substituted benzyl, 3-7 membered heterocyclyl, substituted 3-7membered heterocyclyl, —(C₆-C₁₀) aryl, substituted —(C₆-C₁₀) aryl, 5-6membered heteroaryl, substituted 5-6 membered heteroaryl, —SR⁷, —NR⁷R⁸and —C(═O)—(C₁-C₆) alkyl.

According to some embodiments, R¹ is selected from —(C₁-C₆) alkyl,substituted —(C₁-C₆) alkyl, —(C₃-C₆) cycloalkyl, substituted—(C₃-C₆)cycloalkyl, —(C₂-C₆) alkenyl, substituted —(C₂-C₆)alkenyl,benzyl, substituted benzyl, 3-7 membered heterocyclyl, substituted 3-7membered heterocyclyl, —(C₆-C₁₀) aryl, substituted —(C₆-C₁₀) aryl, 5-6membered heteroaryl, substituted 5-6 membered heteroaryl, —NR⁷R⁸ and—C(═O)—(C₁-C₆) alkyl.

According to some embodiments, a is 1 and b is 0. According to someembodiments, a is 0 and b is 1. According to some embodiments, a and bare both 1.

According to some embodiments, R² is —H.

According to some embodiments, R³ is —H.

According to some embodiments, R⁴ is selected from —H, —(C₁-C₆) alkyland halogen.

According to some embodiments, one of the R³ groups is structurallyconnected to one of the R² groups to form a —CH₂—CH₂— alkylene bridge toproduce a bicyclic ring; e.g.:

According to some embodiments, one of the R³ groups may be structurallyconnected to the R¹ group to form a 5- or 6-membered heterocycle, e.g.,a lactam or imidazole ring, fused to the 1-2 face of the piperidinering; for example:

wherein the R^(1a) moiety represents the residue of the R¹ substituentcovalently bonded to the carbon atom that is alpha to the A moietycarbonyl group, e.g., —H, —(C₁-C₉) hydrocarbyl, or substituted —(C₁-C₉)hydrocarbyl. Examples of ring systems that may be formed by structurallyconnecting the R¹ and R³ groups include indolizin-3-one,quinolizin-4-one, octahydro-1H-pyrido[1,2-c]pyrimidine andoctahydroimidazo[1,5-a]pyridine rings.

According to some embodiments, one of the R³ groups may be structurallyconnected to the R⁴ group to form a 5- or 6-membered carbocyclic orheterocyclic ring fused to the 2-3 face of the piperidine ring; forexample:

According to some embodiments,

is a carbon-carbon single bond.

According to some embodiments, X is —O—.

According to some embodiments, W¹, W² and W³ are independently selectedfrom CH, and C—R¹⁰. According to some embodiments, W¹, W² and W³ are CH.

According to some embodiments, R⁵ is selected from —H, —C₁-C₇hydrocarbyl, —C₃-C₆ heterocyclyl; halogen, —(C₁-C₃) haloalkyl, —OR^(7a),—CN, —NR^(7a)R^(8a), —O(CH₂)_(n)NR^(7a)R^(8a), —O(CH₂)_(n)OR^(8a),—NR^(8a)(CH₂)_(n)NR^(7a)R^(8a), —NR^(8a)(CH₂)_(n)OR⁸a,—C(═O)NR^(7a)R^(8a), —C(═O)OR^(7a), 5-6 membered heteroaryl, andsubstituted 5-6 membered heteroaryl. According to some embodiments, R⁵is selected from —H, —C₁-C₆ alkyl, and halogen. According to someembodiments, R⁵ is —H.

According to some embodiments, R⁶ is selected from 9-10 memberedbicyclic heteroaryl, and substituted 9-10 membered bicyclic heteroaryl.According to some embodiments, R⁶ is selected from:

wherein, when R⁶ is (i), Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are independentlyselected from N and C—R¹², provided that 1, 2 or 3 of Q¹, Q², Q³, Q⁴,Q⁵, Q⁶ and Q⁷ are N, and the remainder of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷are C—R¹²;

when R⁶ is (ii), Q^(1a), Q^(2a), Q^(3a), Q^(4a), Q^(5a), Q^(6a) andQ^(7a) are independently selected from N and C—R¹², provided that 1, 2or 3 of Q^(1a), Q^(2a), Q^(3a), Q^(4a), Q^(5a), Q^(6a) and Q^(7a) are N,and the remainder of Q^(1a), Q²a, Q³a, Q^(4a), Q^(5a), Q^(6a) and Q⁷aare C—R¹²;

when R⁶ is (iii), Q⁸ is selected from O, S, and N—R^(12n), Q⁹, Q¹⁰ andQ¹¹ are independently selected from N and C—R¹², provided that 1 or 2 ofQ⁹, Q¹⁰ and Q¹¹ are N, and the remainder of Q⁹, Q¹⁰ and Q¹¹ are C—R¹²;

when R⁶ is (iv), Q^(8a) is selected from O, S, and N—R^(12n), Q^(9a),Q^(10a) and Q^(11a) are independently selected from N and C—R¹²,provided that 1 or 2 of Q⁹, Q¹⁰ and Q¹¹ are N, and the remainder of Q⁹,Q¹⁰ and Q¹¹ are C—R¹²;

when R⁶ is (v), Q¹², Q¹³ and Q¹⁴ are independently selected from N andC—R¹²; and

when R⁶ is (vi), Q^(12a), Q^(13a) and Q^(14a) are independently selectedfrom N and C—R¹²;

when R⁶ is (vii), Q¹⁵ is selected from N—R^(12n) and C—R¹² and Q¹⁶ isselected from N and C—R¹²; provided that Q¹⁵ and Q¹⁶ are not both C—R¹²;

and wherein each R¹² is independently selected from —H, halogen,—(C₁-C₆) alkyl, —(C₃-C₆) cycloalkyl, —(C₁-C₃) haloalkyl, —O(C₁-C₃)haloalkyl, -5-6 membered heterocyclyl, —OH, —O(C₁-C₆) alkyl,—O(CH₂)_(r)-(5-6 membered heterocyclyl), —O(CH₂)_(r)—O(C₁-C₆) alkyl,—O(CH₂)_(r)—NH(C₁-C₆ alkyl)₂, —NH₂, —CN, —NH(C₁-C₆) alkyl, —N(C₁-C₆alkyl)₂, —NH(CH₂)_(r)—O(C₁-C₆) alkyl, —NH(CH₂)_(r)—N(C₁-C₆ alkyl)₂,—C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl, and —C(═O)N(C₁-C₆ alkyl)₂; wherein ris an integer selected independently from 1, 2, 3, and 4; and

each R^(12n) is independently selected from —H, —(C₁-C₇) hydrocarbyl andsubstituted —(C₁-C₇) hydrocarbyl.

It will be understood that the non-bridgehead ring carbon ring atoms in(i), (ii), (iii), (iv), (v), (vi) and (vii) above (i.e., non-bridgeheadring atoms which are not designated as Q) may optionally be substituted.According to some embodiments, none of these ring carbon ring atoms aresubstituted. According to some embodiments one or two of these ringcarbon ring atoms is substituted. According to some embodiments one ortwo of these ring carbon ring atoms is substituted with a substituentselected from —OH, —(C₁-C₃) alkyl, —O(C₁-C₃)alkyl and halogen. Accordingto some embodiments, one of these ring carbon ring atoms is substitutedwith a substituent selected from —OH, —CH₃, —OCH₃, —F and —Cl.

According to some embodiments, each R¹² is independently selected from—H, halogen, —(C₁-C₆) alkyl, —(C₃-C₆) cycloalkyl, 5-6 memberedheterocyclyl, —OH, —O(C₁-C₆) alkyl, —O(CH₂)_(r)-(5-6 memberedheterocyclyl), —O(CH₂)_(r)—O(C₁-C₆) alkyl, —NH₂, —CN, —NH(C₁-C₆) alkyl,—N(C₁-C₆ alkyl)₂, —NH(CH₂)_(r)—O(C₁-C₆) alkyl, —NH(CH₂)_(r)—N(C₁-C₆alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl, and —C(═O)N(C₁-C₆ alkyl)₂.

According to some embodiments, each R¹² is independently selected from—Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, —CF₃, —OCF₃,—O(CH₂)₂(pyrrolidin-1-yl), —O(CH₂)₃(pyrrolidin-1-yl),—O(CH₂)₂(morpholin-1-yl), —O(CH₂)₃(morpholin-1-yl),—O(CH₂)₂(piperidin-1-yl), —O(CH₂)₃(piperidin-1-yl),—O(CH₂)₂(N-methylpiperazin-1-yl), —O(CH₂)₃(N-methylpiperazin-1-yl),—O(CH₂)₂—OCH₃, —O(CH₂)₃—OCH₃, —O(CH₂)₂—N(CH₃)₂, —O(CH₂)₃—N(CH₃)₂, —NH₂,NHCH₃, N(CH₃)₂, N-methylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-1-yl,and piperidin-1-yl.

According to some embodiments, each R¹² is independently selected from—Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂,—O(CH₂)₂(pyrrolidin-1-yl), —O(CH₂)₃(pyrrolidin-1-yl),—O(CH₂)₂(morpholin-1-yl), —O(CH₂)₃(morpholin-1-yl),—O(CH₂)₂(piperidin-1-yl), —O(CH₂)₃(piperidin-1-yl),—O(CH₂)₂(N-methylpiperazin-1-yl), —O(CH₂)₃(N-methylpiperazin-1-yl),—O(CH₂)₂—OCH₃, —O(CH₂)₃—OCH₃, —O(CH₂)₂—N(CH₃)₂, —O(CH₂)₃—N(CH₃)₂, —NH₂,NHCH₃, N(CH₃)₂, N-methylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-1-yl,and piperidin-1-yl.

According to some embodiments, each R^(12n) is independently selectedfrom —H, benzyl and —(C₁-C₆) alkyl.

According to some embodiments, R⁶ is:

wherein 1 or 2 of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are N, and the remainderof Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹². According to someembodiments, when R⁶ is (i), one of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ is N,and the remainder of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹². Accordingto some embodiments, when R⁶ is (i), Q² is N, and the remainder of Q¹,Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹². According to some embodiments, when R⁶is (i), Q⁶ is N, and Q¹, Q², Q³, Q⁵, Q⁵ and Q⁷ are C—R¹². According tosome embodiments, when R⁶ is (i), Q⁶ is N, Q², Q³, Q⁵, Q⁵ and Q⁷ are CH,and Q¹ is C—R¹², wherein —R¹² is other than —H.

According to some embodiments, R⁶ is selected from 9-10 memberedbicyclic heteroaryl and substituted 9-10 membered bicyclic heteroaryl;provided that, when R⁶ is a 9-membered bicyclic heteroaryl or asubstituted 9-membered bicyclic heteroaryl, the point of attachment ofR⁶ to the aromatic ring containing W¹, W² and W³ is on a 6-membered ringportion of the 9-membered bicyclic heteroaryl or substituted 9-memberedbicyclic heteroaryl.

According to some embodiments, R⁶ is:

wherein one of Q² and Q⁶ is N, and the other of Q² and Q⁶ is C—R¹², andq is an integer selected from 0, 1, 2 and 3. According to someembodiments of i², Q² is N, and Q⁶ is C—R¹². According to someembodiments, Q⁶ is N, and Q² is C—R¹². According to some embodiments, qis selected from 0, 1 and 2. According to some embodiments of i², q is 0or 1. It will be understood that a q value of 0 is the equivalent ofdesignating all R¹² that are bonded to the i² bicyclic heteroaryl atother than Q² and Q⁶ as being —H.

According to some embodiments of i², each R¹² is independently selectedfrom —H, —Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂,—O(CH₂)₂(pyrrolidin-1-yl), —O(CH₂)₃(pyrrolidin-1-yl),—O(CH₂)₂(morpholin-1-yl), —O(CH₂)₃(morpholin-1-yl),—O(CH₂)₂(piperidin-1-yl), —O(CH₂)₃(piperidin-1-yl),—O(CH₂)₂(N-methylpiperazin-1-yl), —O(CH₂)₃(N-methylpiperazin-1-yl),—O(CH₂)₂—OCH₃, —O(CH₂)₃—OCH₃, —O(CH₂)₂—N(CH₃)₂, —O(CH₂)₃—N(CH₃)₂, —NH₂,NHCH₃, N(CH₃)₂, N-methylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-1-yl,and piperidin-1-yl. According to some embodiments of i², each R¹² isindependently selected from —H, —Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, and—OCH₂CH₃.

According to some embodiments of i², each R^(12n) is independentlyselected from —H, benzyl and —C₁-C₆ alkyl.

According to some embodiments, R⁶ is:

wherein one or two of Q², Q⁴ and Q⁶ is N, and the remainder of Q², Q⁴and Q⁶ are C—R¹² and q is an integer selected from 0, 1, 2 and 3.

According to some embodiments of i³, each R¹² is independently selectedfrom —H, halogen, —(C₁-C₆) alkyl, —(C₃-C₆) cycloalkyl, 5-6 memberedheterocyclyl, —OH, —O(C₁-C₆) alkyl, —O(CH₂)_(r)-(5-6 memberedheterocyclyl), —O(CH₂)_(r)—O(C₁-C₆) alkyl, —NH₂, —CN, —NH(C₁-C₆) alkyl,—N(C₁-C₆ alkyl)₂, —NH(CH₂)_(r)—O(C₁-C₆) alkyl, —NH(CH₂)_(r)—N(C₁-C₆alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl, and —C(═O)N(C₁-C₆ alkyl)₂;wherein r is an integer selected from 1, 2, 3 and 4; or a salt thereof.

According to some embodiments of i³, each R¹² is independently selectedfrom —H, —Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂,—O(CH₂)₂(pyrrolidin-1-yl), —O(CH₂)₃(pyrrolidin-1-yl),—O(CH₂)₂(morpholin-1-yl), —O(CH₂)₃(morpholin-1-yl),—O(CH₂)₂(piperidin-1-yl), —O(CH₂)₃(piperidin-1-yl),—O(CH₂)₂(N-methylpiperazin-1-yl), —O(CH₂)₃(N-methylpiperazin-1-yl),—O(CH₂)₂—OCH₃, —O(CH₂)₃—OCH₃, —O(CH₂)₂—N(CH₃)₂, —O(CH₂)₃—N(CH₃)₂, —NH₂,NHCH₃, N(CH₃)₂, N-methylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-1-yl,and piperidin-1-yl. According to some embodiments of i³, each R¹² isindependently selected from —H, —Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, and—OCH₂CH₃.

According to some embodiments of i³, q is 0, 1 or 2. According to someembodiments, q is 0 or 1. It will be understood that a q value of 0 isthe equivalent of designating all R¹² that are bonded to the bicyclicheteroaryl moiety at other than Q², Q⁴ or Q⁶ as being —H.

According to some embodiments of i³, Q² is N, and Q⁴ and Q⁶ are C—R¹².According to some embodiments of i³, Q⁶ is N, and Q² and Q⁴ are C—R¹².According to some embodiments of i³, Q⁴ is N, and Q² and Q⁶ are C—R¹².According to some embodiments of i³, Q² is C—R¹², and Q⁴ and Q⁶ are N.According to some embodiments of i³, Q⁶ is C—R¹², and Q² and Q⁴ are N.According to some embodiments of i³, Q⁴ is C—R¹², and Q² and Q⁶ are N.

According to some embodiments, R⁷ is selected from —H, —(C₁-C₇)hydrocarbyl, substituted —(C₁-C₇) hydrocarbyl, —C(═O)R⁸, and —(C₁-C₆)heteroalkyl.

According to some embodiments, R⁷ is selected from —H, —(C₁-C₆) alkyl,substituted —(C₁-C₆)alkyl, —(C₃-C₆) cycloalkyl, substituted—(C₃-C₆)cycloalkyl, —(C₂-C₆) alkenyl, substituted —(C₂-C₆)alkenyl,benzyl, substituted benzyl, —C(═O)R⁸, and —(C₁-C₆) heteroalkyl.According to some embodiments, R⁷ is selected from —H, and —(C₁-C₆)alkyl.

According to some embodiments, R^(7a) is selected from —H, —(C₁-C₆)alkyl, substituted —(C₁-C₆)alkyl, —(C₃-C₆) cycloalkyl, substituted—(C₃-C₆)cycloalkyl, —(C₂-C₆) alkenyl, substituted —(C₂-C₆)alkenyl,benzyl, substituted benzyl, —C(═O)R⁸, and —(C₁-C₆) heteroalkyl.According to some embodiments, R^(7a) is selected from —H and —(C₁-C₆)alkyl.

According to some embodiments, R⁸ is selected from —H, and —(C₁-C₆)alkyl. According to some embodiments, R⁸ is selected from —H, —CH₃ and—CH₂CH₃.

According to some embodiments, R^(8a) is selected from —H, and —(C₁-C₆)alkyl. According to some embodiments, R^(8a) is selected from —H, —CH₃and —CH₂CH₃.

Another aspect of this application is directed to compounds of FormulaII:

and salts thereof, e.g., pharmaceutically acceptable salts thereof,wherein:

A is selected from —C(═O)— and —SO₂—;

R¹ is selected from —(C₁-C₁₀) hydrocarbyl, substituted —(C₁-C₁₀)hydrocarbyl, 3-7 membered heterocyclyl, substituted 3-7 memberedheterocyclyl, —(C₆-C₁₀) aryl, substituted —(C₆-C₁₀) aryl, 5-6 memberedheteroaryl, substituted 5-6 membered heteroaryl, —NR⁷R⁸, —N(OR⁸)R⁷,—N(SR⁸)R⁷, —SR⁷, —C(═O)—(C₁-C₆) alkyl, and —(C₁-C₆) heteroalkyl;

a and b are independently selected from 0 and 1;

each R² is independently selected from —H and —(C₁-C₄) alkyl;

each R³ is independently selected from —H and —(C₁-C₄) alkyl

R⁴ is selected from —H, —(C₁-C₆) alkyl, ═O, —OH, —O(C₁-C₆) alkyl,halogen and —CN; wherein one of the R³ groups can optionally bestructurally connected to one of the R² groups to form an alkylenebridge to produce a bicyclic ring; or

one of the R³ groups can optionally be structurally connected to the R¹group to form a 5 to 7-membered heterocyclyl ring fused to the 1-2 faceof the piperidine ring; or

one of the R³ groups can optionally be structurally connected to the R⁴group to form a 5 to 7-membered carbocyclic or heterocyclic ring fusedto the 2-3 face of the piperidine ring;

X is selected from —O—, —S—, —SO—, —SO₂—, —NH— and —NR⁹—;

W¹, W² and W³ are independently selected from N, CH, and C—R¹⁰; providedthat W² and W³ are not both N;

R⁵ is selected from —H, —(C₁-C₇) hydrocarbyl, —(C₃-C₆) heterocyclyl;halogen, —(C₁-C₃) haloalkyl, —OR^(7a), —CN, —NR^(7a)R^(8a),—O(CH₂)_(n)NR^(7a)R^(8a), —O(CH₂)_(n)OR^(8a),—NR^(8a)(CH₂)_(n)NR^(7a)R^(8a), —NR^(8a)(CH₂)_(n)OR^(8a),—C(═O)NR^(7a)R^(8a), and —C(═O)OR^(7a), 5-6 membered heteroaryl, andsubstituted 5-6 membered heteroaryl;

n is an integer independently selected from 1, 2, 3, and 4;

R⁶ is selected from:

wherein, when R⁶ is (i), Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are independentlyselected from N and C—R¹², provided that 1, 2 or 3 of Q¹, Q², Q³, Q⁴,Q⁵, Q⁶ and Q⁷ are N, and the remainder of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷are C—R¹²;

when R⁶ is (ii), Q^(1a), Q^(2a), Q^(3a), Q^(4a), Q^(5a), Q^(6a) and Q⁷aare independently selected from N and C—R¹², provided that 1, 2 or 3 ofQ^(1a), Q²a, Q³a, Q^(4a), Q^(5a), Q^(6a) and Q⁷a are N, and theremainder of Q^(1a), Q²a, Q³a, Q^(4a), Q^(5a), Q^(6a) and Q⁷a are C—R¹²;

when R⁶ is (iii), Q⁸ is selected from O, S, and N—R^(12n), Q⁹, Q¹⁰ andQ¹¹ are independently selected from N and C—R¹², provided that 1 or 2 ofQ⁹, Q¹⁰ and Q¹¹ are N, and the remainder of Q⁹, Q¹⁰ and Q¹¹ are C—R¹²;

when R⁶ is (iv), Q⁸a is selected from O, S, and N—R^(12n), Q^(9a),Q^(10a) and Q^(11a) are independently selected from N and C—R¹²,provided that 1 or 2 of Q⁹, Q¹⁰ and Q¹¹ are N, and the remainder of Q⁹,Q¹⁰ and Q¹¹ are C—R¹²;

when R⁶ is (v), Q¹², Q¹³ and Q¹⁴ are independently selected from N andC—R¹²; and

when R⁶ is (vi), Q^(12a), Q^(13a) and Q^(14a) are independently selectedfrom N and C—R¹²;

when R⁶ is (vii), Q¹⁵ is selected from N—R^(12n) and C—R¹² and Q¹⁶ isselected from N and C—R¹²; provided that one of Q¹⁵ and Q¹⁶ are not bothC—R¹²;

R⁷ is selected from —H, —(C₁-C₇) hydrocarbyl, substituted —(C₁-C₇)hydrocarbyl, —C(═O)R⁸, —(C₁-C₆) heteroalkyl, 6 membered aryl, 5-6membered heteroaryl and 5-6 membered heterocyclyl;

R⁸ is selected from —H, and —(C₁-C₆) alkyl, wherein R⁷ can optionally bestructurally connected to R⁸ to form a 5 to 7 membered heterocyclylring;

R^(7a) is selected from —H, —(C₁-C₇) hydrocarbyl, substituted —(C₁-C₇)hydrocarbyl, —C(═O)R⁸, and —(C₁-C₆) heteroalkyl;

R^(8a) is selected from —H, and —(C₁-C₆) alkyl, wherein R^(7a) canoptionally be structurally connected to R^(8a) to form a 5 to 7 memberedheterocyclyl ring;

R⁹ is selected from —(C₁-C₇) hydrocarbyl, wherein R⁹ can optionally bestructurally connected to R⁴ to form a 5 to 7 membered heterocyclylring;

R¹⁰ is selected from —(C₁-C₇) hydrocarbyl, substituted —(C₁-C₇)hydrocarbyl, halogen, —C(═O)—(C₁-C₇) hydrocarbyl, —C(═O)NH₂,—C(═O)NH—(C₁-C₇) hydrocarbyl, —C(═O)N(C₁-C₇) hydrocarbyl)₂, —OH,—O(C₁-C₇) hydrocarbyl, substituted —O(C₁-C₇) hydrocarbyl, —(C₃-C₆)heterocyclyl, substituted —(C₃-C₆) heterocyclyl —CN, —NH₂,—NH(C₁-C₆)alkyl, —N(C₁-C₆ alkyl)₂, —NH(CH₂)_(m)—R¹¹, —N(C₁-C₆alkyl)(CH₂)_(m)—R¹¹, —O—(CH₂)_(m)—R¹¹, and —(C₁-C₆) heteroalkyl;

m is an integer selected independently from 1, 2, 3, and 4;

R¹¹ is selected from —O(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂,—(C₃-C₆)heterocyclyl and substituted —(C₃-C₆) heterocyclyl;

each R¹² is independently selected from —H, halogen, —(C₁-C₆) alkyl,—(C₃-C₆) cycloalkyl, —(C₁-C₃) haloalkyl, —O(C₁-C₃) haloalkyl, 5-6membered heterocyclyl, —OH, —O(C₁-C₆) alkyl, —O(CH₂)_(r)-(5-6 memberedheterocyclyl), —O(CH₂)_(r)—O(C₁-C₆) alkyl, —O(CH₂)_(r)—N(C₁-C₆ alkyl)₂,—NH₂, —CN, —NH(C₁-C₆) alkyl, —N(C₁-C₆ alkyl)₂, —NH(CH₂)_(r)—O(C₁-C₆)alkyl, —NH(CH₂)_(r)—N(C₁-C₆ alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl,and —C(═O)N(C₁-C₆ alkyl)₂; wherein r is an integer selectedindependently from 1, 2, 3, and 4; and each R^(12n) is independentlyselected from —H, —(C₁-C₇) hydrocarbyl and substituted —(C₁-C₇)hydrocarbyl.

According to some embodiments, A is —C(═O)—. According to otherembodiments, A is —SO₂—.

According to some embodiments, a and b are both 0, thus making the ringcontaining these elements a 4-membered ring. According to otherembodiments, a is 0 and b is 1, or a is 1 and b is 0, thus making thering containing these elements a 5-membered ring. According to someembodiments, a and b are both 1, thus making the ring containing theseelements a 6-membered ring.

According to some embodiments, each R² is —H or —CH₃. According to otherembodiments each R² is —H.

According to some embodiments, each R¹² is independently selected from—H, halogen, —(C₁-C₆) alkyl, —(C₃-C₆) cycloalkyl, 5-6 memberedheterocyclyl, —OH, —O(C₁-C₆) alkyl, —O(CH₂)_(r)-(5-6 memberedheterocyclyl), —O(CH₂)_(r)—O(C₁-C₆) alkyl, —NH₂, —CN, —NH(C₁-C₆) alkyl,—N(C₁-C₆ alkyl)₂, —NH(CH₂)_(r)—O(C₁-C₆) alkyl, —NH(CH₂)_(r)—N(C₁-C₆alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl, and —C(═O)N(C₁-C₆ alkyl)₂.

According to some embodiments, R¹ is selected from —(C₁-C₁₀)hydrocarbyl, substituted —(C₁-C₁₀) hydrocarbyl, 3-7 memberedheterocyclyl, substituted 3-7 membered heterocyclyl, —(C₆-C₁₀) aryl,substituted —(C₆-C₁₀) aryl, 5-6 membered heteroaryl, substituted 5-6membered heteroaryl, —NR⁷R⁸, —N(OR⁸)R⁷, and —C(═O)—(C₁-C₆) alkyl and—(C₁-C₆) heteroalkyl.

According to some embodiments, R¹ is selected from —(C₁-C₆) alkyl,substituted —(C₁-C₆) alkyl, —(C₁-C₆) cycloalkyl, substituted —(C₁-C₆)cycloalkyl, —C(═O)—(C₁-C₆) alkyl, —S(C₁-C₆) alkyl, substituted —S(C₁-C₆)alkyl, 5-6 membered heterocyclyl, substituted 5-6 membered heterocyclyl,NH₂, —NH(C₁-C₆) alkyl, —N((C₁-C₆) alkyl)₂, —NH—O(C₁-C₆) alkyl,—(CH₂)_(n)O(C₁-C₆) alkyl, —(CH₂)_(n)OH, —(CH₂)_(n)SO₂(C₁-C₆)alkyl,—(C₆-C₁₀) aryl, substituted —(C₆-C₁₀) aryl and —(CH₂)_(n)—CN.

According to some embodiments, R¹ is selected from —(C₁-C₆) alkyl,substituted —(C₁-C₆) alkyl, —(C₁-C₆) cycloalkyl, substituted —(C₁-C₆)cycloalkyl, —C(═O)—(C₁-C₆) alkyl, 5-6 membered heterocyclyl, substituted5-6 membered heterocyclyl, NH₂, —NH(C₁-C₆) alkyl, —N((C₁-C₆) alkyl)₂,—NH—O(C₁-C₆) alkyl, —(CH₂)_(n)O(C₁-C₆) alkyl, —(CH₂)_(n)OH,—(CH₂)_(n)SO₂(C₁-C₆)alkyl, —(C₆-C₁₀) aryl, substituted —(C₆-C₁₀) aryland —(CH₂)_(n)—CN.

According to other embodiments, R¹ is selected from —CH₃, —CH₂CH₃,—(CH₂)₂CH₃, —(CH₂)₃CH₃, —(CH₂)₄CH₃, —CH(CH₃)₃, —C(CH₃)₃, cyclopropyl,substituted cyclopropyl, cyclobutyl, substituted cyclobutyl,cyclopentyl, —C(═O)CH₃, —C(═O)CH₂CH₃, —NH—OH, —NH—OCH₃, —NH—OCH₂CH₃,—N(CH₃)—OCH₃, —NH₂, —NHCH₃, —NH—CH₂CH₃, —NH(CH₂)₂—CH₃, —NH(CH₂)₃—CH₃,—NH(CH₂)₄—CH₃, —NH(CH₂)₅—CH₃, —N(CH₃)₂, —N(Et)₂, —NH—CH(CH₃)₂,—NH—OCH₂CH₃, —NHSCH₃, —NHSCH₂CH₃, —SCH₃, —SCH₂CH₃, —SCH(CH₃)₂,tetrahydrofuranyl, substituted tetrahydrofuranyl, furanyl, substitutedfuranyl, dioxolanyl, substituted dioxolanyl, tetrahydropyrrolyl,piperidinyl, morpholinyl, tetrahydropyranyl, thiophenyl,tetrahydrothiophenyl, sulfolanyl, tetrahydroisoxazolidinyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazole, pyrydyl, substitutedpyridyl, quinolyl, substituted quinolyl, phenyl, substituted phenyl,—CH₂—OCH₃, —(CH₂)₂—OCH₃, and —(CH₂)₃—OCH₃.

According to other embodiments, R¹ is selected from —CH₃, —CH₂CH₃,—(CH₂)₂CH₃, —(CH₂)₃CH₃, —(CH₂)₄CH₃, —CH(CH₃)₃, —C(CH₃)₃, cyclopropyl,substituted cyclopropyl, cyclobutyl, substituted cyclobutyl,cyclopentyl, —C(═O)CH₃, —C(═O)CH₂CH₃, —NH—OH, —NH—OCH₃, —NH—OCH₂CH₃,—N(CH₃)—OCH₃, —NH₂, —NHCH₃, —NH—CH₂CH₃, —NH(CH₂)₂—CH₃, —NH(CH₂)₃—CH₃,—NH(CH₂)₄—CH₃, —NH(CH₂)₅—CH₃, —N(CH₃)₂, —N(Et)₂, —NH—CH(CH₃)₂,—NH—OCH₂CH₃, tetrahydrofuranyl, substituted tetrahydrofuranyl, furanyl,substituted furanyl, dioxolanyl, substituted dioxolanyl,tetrahydropyrrolyl, piperidinyl, morpholinyl, tetrahydropyranyl,thiophenyl, tetrahydrothiophenyl, sulfolanyl, tetrahydroisoxazolidinyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazole, pyrydyl,substituted pyridyl, quinolyl, substituted quinolyl, phenyl, substitutedphenyl, —CH₂—OCH₃, —(CH₂)₂—OCH₃, and —(CH₂)₃—OCH₃.

According to some embodiments, when R¹ is substituted cyclopropyl, thecyclopropyl ring is substituted with 1 or two substituents selected from—OH, —CH₂, —OH, —C(═O)NH₂, —NH₂, —CH₃, —CN, and —CF₃.

According to some embodiments, when R¹ is tetrahydrofuranyl, it istetrahydro-furan-2-yl or tetrahydrofuran-3-yl. According to someembodiments, when R¹ is substituted tetrahydrofuranyl it is2-methyltetrahydrofuran-2-yl, 5-methyltetrahydrofuran-2-yl,2,5-dimethyltetrahydrofuran-2-yl or tetrahydrofuran-4-one-2-yl, or4,4-difluorotetrahydrofuran-2-yl.

According to some embodiments, when R¹ is furanyl, it is 2-furanyl or3-furanyl.

According to some embodiments, when R¹ is substituted furanyl, it is2-methylfuran-2-yl, 5-methylfuran-2-yl, or 2,5-dimethylfuran-2-yl.

According to some embodiments, when R¹ is dioxolanyl, it is1,3-dioxolan-2-yl. According to some embodiments, when R¹ is substituteddioxolanyl it is 2-methyl-1,3-dioxolan-2-yl.

According to some embodiments, when R¹ is tetrahydroisoxazolidine, it istetra-hydroisoxazolidin-2-yl. According to some embodiments, when R¹ istetrahydropyrrolyl, it is tetrahydropyrrol-1-yl. According to someembodiments, when R¹ is morpholinyl, it is morpholin-1-yl. According tosome embodiments, when R¹ is piperidinyl, it is piperidin-1-yl.According to some embodiments, when R¹ is furanyl, it is 2-furanyl or3-furanyl. According to some embodiments, when R¹ is thiophenyl, it is2-thiophenyl or 2-thiophenyl. According to some embodiments, when R¹ istetrahydrothiophenyl, it is 2-tetrahydrothiophenyl or2-tetrahydrothiophenyl. According to some embodiments, when R¹ issulfolanyl, it is sulfolan-2-yl or sulfolan-3-yl. According to someembodiments, when R¹ is oxazolyl, it is oxazol-1-yl, oxazol-2-one-1-yloxazol-2-yl or oxazol-5-yl. According to some embodiments, when R¹ isisoxazolyl, it is isoxazol-1-yl, isoxazol-3-yl or isoxazol-5-yl.According to some embodiments, when R¹ is imidazolyl, it isimidazol-2-yl or imidazol-5-yl. According to some embodiments, when R¹is thiazolyl, it is thiazol-2-yl or thiazol-5-yl. According to someembodiments, when R¹ is isothiazolyl, it is isothiazol-3-yl orisothiazol-5-yl. According to some embodiments, when R¹ is pyridyl, itis 2-pyridyl, 3-pyridyl, or 4-pyridyl. According to some embodiments,when R¹ is substituted quinolyl, it is quinolin-1-yl, quinolin-2-yl orquinolin-3-yl. According to some embodiments, when R¹ is substitutedphenyl, it is 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, or2,5-dimethylphenyl. According to some embodiments, R¹ is selected fromthe moieties depicted in Table 1 and Table 1a below

TABLE 1 A selection of some suitable R¹ moieties. —CH₃ —NHCH₂CH₃—CH(CH₃)CH₃ —CH₂—OH —CH₂CH₃ —NHCH(CH₃)CH₃ —CH₂—CN —NHCH₃ —(CH₂)₂CH₃—C(═O)CH₃ —CH(CH₃)₂—OH —CF₃ —(CH(CH₃)₃ —CH—SO₂—CH₃ —CF₂—CH₃ —CH₂—OCH₃—NH₂ —NH—OH —NH—OCH₂CH₃ —N(CH₃)—OCH₃ —CH₂CH(CH₃)CH₃ —CH(CH₃)—OCH₃—NH—OCH₃ —N(CH₃)₂

TABLE 1a A Selection of Some Additional Suitable R¹ moieties.

—O-t-Butyl

According to some embodiments each R³ is —H or —CH₃. According to otherembodiments, each R³ is —H.

According to some embodiments, R⁴ is selected from —H, —(C₁-C₆)alkyl,—OH, —O(C₁-C₆)alkyl, —CN and halogen According to other embodiments, R⁴is selected from —H, —CH₃, —OH, —OCH₃, —F, —Cl, and —CN. According tosome embodiments, R⁴ is halogen or —H. According to some embodiments, R⁴is —F or —H. According to some embodiments, R⁴ is —H.

According to some embodiments, one of the R³ groups can optionally bestructurally connected to one of the R² groups to form a C₂-C₃ alkylenebridge to produce a bicyclic ring. According to some embodiments, one ofthe R³ groups is structurally connected to one of the R² groups to forma —CH₂—CH₂— bridge to produce a bicyclic ring; for example:

According to some embodiments, one of the R³ groups, can optionally bestructurally connected to the R¹ group to form a 5 to 7-memberedheterocyclyl ring fused to the 1-2 face of the piperidine ring.According to some embodiments, one of the R³ groups is structurallyconnected to the R¹ group to form a 5- or 6-membered heterocycle, e.g.,a lactam or imidadole ring fused to the 1-2 face of the piperidine ring;for example:

wherein the R^(1a) moiety represents the residue of the R¹ substituentcovalently bonded to the carbon atom that is alpha to the A moietycarbonyl group, e.g., —H, —(C₁-C₉) hydrocarbyl, or substituted —(C₁-C₉)hydrocarbyl. Examples of ring systems that may be formed by structurallyconnecting the R¹ and R³ groups include indolizin-3-one,quinolizin-4-one, octahydro-1H-pyrido[1,2-c]pyrimidine andoctahydroimidazo[1,5-a]pyridine rings.

According to some embodiments, one of the R³ groups can optionally bestructurally connected to the R⁴ group to form a 5-7 memberedcarbocyclic or heterocyclic ring fused to the 2-3 face of the piperidinering. According to some embodiments, one of the R³ groups can optionallybe structurally connected to the R⁴ group to form a 5-memberedcarbocyclic ring, a 6-membered carbocyclic ring or a 7-memberedcarbocyclic ring fused to the 2-3 face of the piperidine ring. Accordingto some embodiments, one of the R³ groups can optionally be structurallyconnected to the R⁴ group to form a 5-membered heterocyclic ring, a6-membered heterocyclic ring or a 7-membered heterocyclic ring fused tothe 2-3 face of the piperidine ring. According to some embodiments, oneof the R³ groups is structurally connected to the R⁴ group to form a5-membered carbocyclic or heterocyclic ring fused to the 2-3 face of thepiperidine ring; for example:

According to some embodiments, X is selected from —O—, —S—, —SO—, and—SO₂—. According to some embodiments, X is selected from —O—, —S— and—SO₂—. According to some embodiments, X is selected from —O— and —S—.According to some embodiments, X is —O—. According to some embodiments,X is —S—. According to some embodiments, X is —SO—. According to someembodiments, X is —SO₂—. According to some embodiments, X is —NR⁹—.According to some embodiments, X is —NH—.

According to some embodiments, R⁹ is —(C₁-C₆) alkyl. According to someembodiments, the R⁹ group can optionally be structurally connected tothe R⁴ group to form a 5 to 7-membered heterocyclyl ring. According tosome embodiments, the R⁹ group can optionally be structurally connectedto the R⁴ group to form a 5-membered heterocyclyl ring. According tosome embodiments, the R⁹ group can optionally be structurally connectedto the R⁴ group to form a 6-membered heterocyclyl ring. According tosome embodiments, the R⁹ group can optionally be structurally connectedto the R⁴ group to form a 7-membered heterocyclyl ring.

According to some embodiments, W¹, W² and W³ are independently selectedfrom CH, and C—R¹⁰. According to some embodiments, W¹, W² and W³ are allCH. According to some embodiments, one of W¹ and W² is N, and W³ and theother of W¹ and W² is CH or C—R¹⁰. According to some embodiments, W¹ isN, and W² and W³ are CH or C—R¹⁰. According to some embodiments, W¹ isN, and W² and W³ are CH. According to some embodiments, W¹ and W² are Nand W³ is CH or C—R¹⁰. According to some embodiments, W¹ and W² are Nand W³ is CH. According to some embodiments, W¹ and W² are CH or C—R¹⁰,and W³ is N. According to some embodiments, W¹ and W² are CH, and W³ isN.

According to some embodiments, each R¹⁰ is independently selected from—F, —Cl, —CN, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, —C(═O)—(C₁-C₆) alkyl,—C(═O)—(C₃-C₆) cycloalkyl, C(═O)NH₂, —C(═O)NH—C₁-C₆ alkyl, —C(═O)N(C₁-C₆alkyl)₂, —O(C₁-C₆)alkyl, —(C₁-C₆)alkyl, —OH, —(C₅-C₆) heterocyclyl,substituted —(C₅-C₆) heterocyclyl, —O—(CH₂)_(m)—O(C₁-C₆)alkyl,—O(CH₂)_(n)-(C₅-C₆) heterocyclyl, substituted O—(CH₂)_(m)—(C₅-C₆)heterocyclyl, —NH₂, —N((C₁-C₆)alkyl)₂, —NH—(CH₂)_(m)—O—(C₁-C₆)alkyl, and—NH—(CH₂)_(m)—N((C₁-C₆)alkyl)₂.

According to some embodiments, each R¹⁰ is independently selected from—F, —Cl, —CN, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, —OH, —O(C₁-C₆)alkyl,NH₂, —NH(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂, —C(═O)(C₁-C₆)alkyl,—C(═O)—(C₃-C₆) cycloalkyl, —C(═O)NH₂, —CF₃, —O(CH₂)_(m)-morpholine-1-yl,—O(CH₂)_(m)-pyrrolidline-1-yl, —O(CH₂)_(m)-4-methylpiperidine-1-yl,—O(CH₂)_(m)—OCH₃, morpholine-1-yl, 4-methylpiperidine-1-yl,—NH(CH₂)_(m)—OCH₃, and —NH(CH₂)_(m)—N(CH₃)₂.

According to some embodiments, each R¹⁰ is independently selected from—F, —Cl, —CN, —CH₃, —CH₂CH₃, —OCH₃, and —OCH₂CH₃.

According to some embodiments, R⁵ is selected from —H, —(C₁-C₆) alkyl,—(C₃-C₆) cycloalkyl, and halogen. According to some embodiments, R⁵ is—H.

According to some embodiments, R⁶ may be selected from the bicyclic ringsystems shown in Table 1b, wherein R^(12n) is as defined herein, and thenon-bridgehead carbon atoms in the bicyclic ring systems may optionallybe substituted. According to some embodiments, 0, 1, 2 or 3 of thenon-bridgehead carbon atoms in the ring systems shown in Table 1b may besubstituted by R¹² substituents as R¹² is defined herein

TABLE 1b A selection of some suitable R⁶ moieties.

According to some embodiments, R⁶ is:

wherein 1 or 2 of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are N, and the remainderof Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹². According to someembodiments, when R⁶ is (i), one of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ is N,and the remainder of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹². Accordingto some embodiments, when R⁶ is (i), Q² is N, and the remainder of Q¹,Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹². According to some embodiments, when R⁶is (i), Q⁶ is N, and Q¹, Q², Q³, Q⁵, Q⁵ and Q⁷ are C—R¹². According tosome embodiments, when R⁶ is (i), Q⁶ is N, Q², Q³, Q⁵, Q⁵ and Q⁷ are CH,and Q¹ is C—R¹², wherein —R¹² is other than —H.

It will be understood that, when R⁶ is (iii), (iv), (v), (vi) or (vii),the non-bridgehead ring carbon ring atoms (i.e., non-bridgehead ringatoms which are not designated as Q) may optionally be substituted.According to some embodiments, none of these ring carbon ring atoms aresubstituted. According to some embodiments, one or two of these ringcarbon ring atoms may be substituted with a substituent selected from—OH, —(C₁-C₃) alkyl, —O(C₁-C₃)alkyl and halogen. According to someembodiments, one of these ring carbon ring atoms is substituted with asubstituent selected from —OH, —CH₃, —OCH₃, —F and —Cl.

According to some embodiments, R⁶ is:

wherein one of Q² and Q⁶ is N, and the other of Q² and Q⁶ is C—R¹², andq is an integer selected from 0, 1, 2 and 3. According to someembodiments of i², Q² is N, and Q⁶ is C—R¹². According to someembodiments, Q⁶ is N, and Q² is C—R¹². According to some embodiments, qis selected from 0, 1 and 2. According to some embodiments of i², q is 0or 1. It will be understood that a q value of 0 is the equivalent ofdesignating all R¹² that are bonded to the i² bicyclic heteroaryl atother than Q² and Q⁶ as being —H.

According to some embodiments of i², each R¹² is independently selectedfrom —H, —Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂,—O(CH₂)₂(pyrrolidin-1-yl), —O(CH₂)₃(pyrrolidin-1-yl),—O(CH₂)₂(morpholin-1-yl), —O(CH₂)₃(morpholin-1-yl),—O(CH₂)₂(piperidin-1-yl), —O(CH₂)₃(piperidin-1-yl),—O(CH₂)₂(N-methylpiperazin-1-yl), —O(CH₂)₃(N-methylpiperazin-1-yl),—O(CH₂)₂—OCH₃, —O(CH₂)₃—OCH₃, —O(CH₂)₂—N(CH₃)₂, —O(CH₂)₃—N(CH₃)₂, —NH₂,NHCH₃, N(CH₃)₂, N-methylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-1-yl,and piperidin-1-yl. According to some embodiments of i², each R¹² isindependently selected from —H, —Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃,and —OCH(CH₃)₂.

According to some embodiments of i², each R^(12n) is independentlyselected from —H, benzyl and —C₁-C₆ alkyl.

According to some embodiments, R⁶ is:

wherein one or two of Q², Q⁴ and Q⁶ is N, and the remainder of Q², Q⁴and Q⁶ are C—R¹², and q is an integer selected from 0, 1, 2 and 3.

According to some embodiments of i³, each R¹² is independently selectedfrom —H, halogen, —(C₁-C₆) alkyl, —(C₃-C₆) cycloalkyl, 5-6 memberedheterocyclyl, —OH, —O(C₁-C₆) alkyl, —O(CH₂)_(r)-(5-6 memberedheterocyclyl), —O(CH₂)_(r)—O(C₁-C₆) alkyl, —NH₂, —CN, —NH(C₁-C₆) alkyl,—N(C₁-C₆ alkyl)₂, —NH(CH₂)_(r)—O(C₁-C₆) alkyl, —NH(CH₂)_(r)—N(C₁-C₆alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl, and —C(═O)N(C₁-C₆ alkyl)₂;wherein r is an integer selected from 1, 2, 3 and 4; or a salt thereof.

According to some embodiments of i³, each R¹² is independently selectedfrom —H, —Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂,—O(CH₂)₂(pyrrolidin-1-yl), —O(CH₂)₃(pyrrolidin-1-yl),—O(CH₂)₂(morpholin-1-yl), —O(CH₂)₃(morpholin-1-yl),—O(CH₂)₂(piperidin-1-yl), —O(CH₂)₃(piperidin-1-yl),—O(CH₂)₂(N-methylpiperazin-1-yl), —O(CH₂)₃(N-methylpiperazin-1-yl),—O(CH₂)₂—OCH₃, —O(CH₂)₃—OCH₃, —O(CH₂)₂—N(CH₃)₂, —O(CH₂)₃—N(CH₃)₂, —NH₂,NHCH₃, N(CH₃)₂, N-methylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-1-yl,and piperidin-1-yl. According to some embodiments of i³, each R¹² isindependently selected from —H, —Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, and—OCH₂CH₃.

According to some embodiments of i³, q is 0, 1 or 2. According to someembodiments, q is 0 or 1. It will be understood that a q value of 0 isthe equivalent of designating all R¹² that are bonded to the bicyclicheteroaryl moiety at other than Q², Q⁴ or Q⁶ as being —H.

According to some embodiments of i³, Q² is N, and Q⁴ and Q⁶ are C—R¹².According to some embodiments of i³, Q⁶ is N, and Q² and Q⁴ are C—R¹².According to some embodiments of i³, Q⁴ is N, and Q² and Q⁶ are C—R¹².According to some embodiments of i³, Q² is C—R¹², and Q⁴ and Q⁶ are N.According to some embodiments of i³, Q⁶ is C—R¹², and Q² and Q⁴ are N.According to some embodiments of i³, Q⁴ is C—R¹², and Q² and Q⁶ are N.

According to some embodiments, R⁷ is selected from —H, —(C₁-C₇)hydrocarbyl, substituted —(C₁-C₇) hydrocarbyl, —C(═O)R⁸, and —(C₁-C₆)heteroalkyl.

According to some embodiments, each R¹² is independently selected from—H, —Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂,—O(CH₂)₂(pyrrolidin-1-yl), —O(CH₂)₃(pyrrolidin-1-yl),—O(CH₂)₂(morpholin-1-yl), —O(CH₂)₃(morpholin-1-yl),—O(CH₂)₂(piperidin-1-yl), —O(CH₂)₃(piperidin-1-yl),—O(CH₂)₂(N-methylpiperazin-1-yl), —O(CH₂)₃(N-methylpiperazin-1-yl),—O(CH₂)₂—OCH₃, —O(CH₂)₃—OCH₃, —O(CH₂)₂—N(CH₃)₂, —O(CH₂)₃—N(CH₃)₂, —NH₂,NHCH₃, N(CH₃)₂, N-methylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-1-yl,piperidin-1-yl, —CF₃, —OCF₃, cyclopropyl, —OH, —C(═O)NH₂, —NH(CH₂)₂pyrrolidin-1-yl, —NH(CH₂)₂N(CH₃)₂, —NH(CH₂)₂₀CH₃ and —CN.

According to some embodiments, each R¹² is independently selected from—H, —Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂,—O(CH₂)₂(pyrrolidin-1-yl), —O(CH₂)₃(pyrrolidin-1-yl),—O(CH₂)₂(morpholin-1-yl), —O(CH₂)₃(morpholin-1-yl),—O(CH₂)₂(piperidin-1-yl), —O(CH₂)₃(piperidin-1-yl),—O(CH₂)₂(N-methylpiperazin-1-yl), —O(CH₂)₃(N-methylpiperazin-1-yl),—O(CH₂)₂—OCH₃, —O(CH₂)₃—OCH₃, —O(CH₂)₂—N(CH₃)₂, —O(CH₂)₃—N(CH₃)₂, —NH₂,NHCH₃, N(CH₃)₂, N-methylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-1-yland piperidin-1-yl.

According to some embodiments, R¹² is selected from —F, —Cl, —CH₃, and—OCH₃.

According to some embodiments, R^(12n) is selected from —H, benzyl and—(C₁-C₆) alkyl.

Another aspect of this application is directed to compounds of FormulaIII:

and salts thereof, e.g., pharmaceutically acceptable salts thereof,wherein:

R¹ is selected from —(C₁-C₁₀) hydrocarbyl, substituted —(C₁-C₁₀)hydrocarbyl, 3-7 membered heterocyclyl, substituted 3-7 memberedheterocyclyl, —(C₆-C₁₀) aryl, substituted —(C₆-C₁₀) aryl, 5-6 memberedheteroaryl, substituted 5-6 membered heteroaryl, —NR⁷R⁸, —N(OR⁸)R⁷,—N(SR)R⁷, —S—R⁷ and —C(═O)—(C₁-C₆) alkyl and —(C₁-C₆) heteroalkyl;

X is selected from —O—, —S—, —SO—, —SO₂—, and —NR⁹—;

W¹ is CH or C—R¹⁰;

R⁴ is halogen or —H;

R⁵ is selected from —H, —(C₁-C₇) hydrocarbyl, —(C₃-C₆) heterocyclyl;halogen, —(C₁-C₃) haloalkyl, —OR^(7a), —CN, —NR^(7a)R^(8a),—O(CH₂)_(n)NR^(7a)R^(8a), —O(CH₂)_(n)OR^(8a),—NR^(8a)(CH₂)_(n)NR^(7a)R^(8a), —NR^(8a)(CH₂)_(n)OR^(8a),—C(═O)NR^(7a)R^(8a), —C(═O)OR^(7a), 5-6 membered heteroaryl, andsubstituted 5-6 membered heteroaryl;

n is an integer selected independently from 1, 2, 3, and 4;

Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are independently selected from N andC—R¹², provided that 1 or 2 of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are N, andthe remainder of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹²;

R⁷ is selected from —H, —(C₁-C₇) hydrocarbyl, substituted —(C₁-C₇)hydrocarbyl, —C(═O)R⁸, —(C₁-C₆) heteroalkyl, 6 membered aryl, 5-6membered heteroaryl and 5-6 membered heterocyclyl;

R⁸ is selected from —H, and —(C₁-C₆) alkyl, wherein R⁷ can optionally bestructurally connected to R⁸ to form a 5 to 7 membered heterocyclylring;

R^(7a) is selected from —H, —(C₁-C₇) hydrocarbyl, substituted —(C₁-C₇)hydrocarbyl, —C(═O)R⁸, and —(C₁-C₆) heteroalkyl;

R^(8a) is selected from —H, and —(C₁-C₆) alkyl, wherein R^(7a) canoptionally be structurally connected to R^(8a) to form a 5 to 7 memberedheterocyclyl ring;

R⁹ is selected from —(C₁-C₆) alkyl, wherein R⁹ can optionally bestructurally connected to R⁴ to form a 5 to 7 membered heterocyclylring;

R¹⁰ is selected from —F, —Cl, —CN, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl,—OH, —O—(C₁-C₆)alkyl, NH₂, —NH(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂,—C(═O)(C₁-C₆)alkyl, —C(═O)—(C₃-C₆) cycloalkyl, —C(═O)NH₂, —CF₃,—O(CH₂)_(m)-morpholine-1-yl, —O(CH₂)_(m)-pyrrolidline-1-yl,—O(CH₂)_(m)-4-methylpiperidine-1-yl, —O(CH₂)_(m)—OCH₃, morpholine-1-yl,4-methylpiperidine-1-yl, —NH(CH₂)_(m)—OCH₃, and —NH(CH₂)_(m)—N(CH₃)₂;

m is an integer selected independently from 1, 2, 3, and 4;

R¹¹ is selected from —O(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂,—(C₃-C₆)heterocyclyl and substituted —(C₃-C₆) heterocyclyl; and

each R¹² is independently selected from —H, halogen, —(C₁-C₆) alkyl,—(C₃-C₆) cycloalkyl, —(C₁-C₃) haloalkyl, —O(C₁-C₃) haloalkyl, 5-6membered heterocyclyl, —OH, —O(C₁-C₆) alkyl, —O(CH₂)_(p)-(5-6 memberedheterocyclyl), —O(CH₂)_(r)—O(C₁-C₆) alkyl, —O(CH₂)_(r)—N(C₁-C₆ alkyl)₂,—NH₂, —CN, —NH(C₁-C₆) alkyl, —N(C₁-C₆ alkyl)₂, —NH(CH₂)_(r)—O(C₁-C₆)alkyl, —NH(CH₂)_(r)—N(C₁-C₆ alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl,and —C(═O)N(C₁-C₆ alkyl)₂; wherein r is an integer selectedindependently from 1, 2, 3, and 4.

According to some embodiments, R¹ is selected from —(C₁-C₁₀)hydrocarbyl, substituted —(C₁-C₁₀) hydrocarbyl, 3-7 memberedheterocyclyl, substituted 3-7 membered heterocyclyl, —(C₆-C₁₀) aryl,substituted —(C₆-C₁₀) aryl, 5-6 membered heteroaryl, substituted 5-6membered heteroaryl, —NR⁷R⁸, —N(OR⁸)R⁷, and —C(═O)—(C₁-C₆) alkyl and—(C₁-C₆) heteroalkyl.

According to some embodiments, R¹ is selected from —(C₁-C₆) alkyl,substituted —(C₁-C₆) alkyl, —(C₁-C₆) cycloalkyl, substituted —(C₁-C₆)cycloalkyl, —C(═O)—(C₁-C₆) alkyl, 5-6 membered heterocyclyl, substituted5-6 membered heterocyclyl, —NH₂, —NH(C₁-C₆) alkyl, —N((C₁-C₆) alkyl)₂,—NH—O(C₁-C₆) alkyl, —NH—S(C₁-C₆) alkyl, —S(C₁-C₆) alkyl,—(CH₂)_(n)O(C₁-C₆) alkyl, —(CH₂)_(n)OH, —(CH₂)_(n)SO₂(C₁-C₆)alkyl,—(C₆-C₁₀) aryl, substituted —(C₆-C₁₀) aryl, and —(CH₂)_(n)-CN.

According to some embodiments, R¹ is selected from —(C₁-C₆) alkyl,substituted —(C₁-C₆) alkyl, —(C₁-C₆) cycloalkyl, substituted —(C₁-C₆)cycloalkyl, —C(═O)—(C₁-C₆) alkyl, 5-6 membered heterocyclyl, substituted5-6 membered heterocyclyl, —NH₂, —NH(C₁-C₆) alkyl, —N((C₁-C₆) alkyl)₂,—NH—O(C₁-C₆) alkyl, —(CH₂)_(n)O(C₁-C₆) alkyl, —(CH₂)_(n)OH,—(CH₂)_(n)SO₂(C₁-C₆)alkyl, —(C₆-C₁₀) aryl, substituted —(C₆-C₁₀) aryl,and —(CH₂)_(n)-CN.

According to other embodiments, R¹ is selected from —CH₃, —CH₂CH₃,—(CH₂)₂CH₃, —(CH₂)₃CH₃, —(CH₂)₄CH₃, —CH(CH₃)₃, —C(CH₃)₃, cyclopropyl,substituted cyclopropyl, cyclobutyl, substituted cyclobutyl,cyclopentyl, —C(═O)CH₃, —C(═O)CH₂CH₃, —NH—OH, —NH—OCH₃, —NH—OCH₂CH₃,—N(CH₃)—OCH₃, —NH₂, —NHCH₃, —NH—CH₂CH₃, —NH(CH₂)₂—CH₃, —NH(CH₂)₃—CH₃,—NH(CH₂)₄—CH₃, —NH(CH₂)₅—CH₃, —N(CH₃)₂, —N(Et)₂, —NH—CH(CH₃)₂,—NH—OCH₂CH₃, tetrahydrofuranyl, substituted tetrahydrofuranyl, furanyl,substituted furanyl, dioxolanyl, substituted dioxolanyl,tetrahydropyrrolyl, piperidinyl, morpholinyl, tetrahydropyranyl,thiophenyl, tetrahydrothiophenyl, sulfolanyl, tetrahydroisoxazolidinyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazole, pyrydyl,substituted pyridyl, quinolyl, substituted quinolyl, phenyl, substitutedphenyl, —CH₂—OCH₃, —(CH₂)₂—OCH₃, and —(CH₂)₃—OCH₃.

According to other embodiments, R¹ is selected from —CH₃, —CH₂CH₃,—(CH₂)₂CH₃, —(CH₂)₃CH₃, —(CH₂)₄CH₃, —CH(CH₃)₃, —C(CH₃)₃, cyclopropyl,substituted cyclopropyl, cyclobutyl, substituted cyclobutyl,cyclopentyl, —C(═O)CH₃, —C(═O)CH₂CH₃, —NH—OH, —NH—OCH₃, —NH—OCH₂CH₃,—N(CH₃)—OCH₃, —NH₂, —NHCH₃, —NH—CH₂CH₃, —NH(CH₂)₂—CH₃, —NH(CH₂)₃—CH₃,—NH(CH₂)₄—CH₃, —NH(CH₂)₅—CH₃, —N(CH₃)₂, —N(Et)₂, —NH—CH(CH₃)₂,—NH—OCH₂CH₃, —NH—SCH₂CH₃, —NH—SCH₃, —SCH₃, —SCH₂CH₃, —SCH(CH₃)₂,tetrahydrofuranyl, substituted tetrahydrofuranyl, furanyl, substitutedfuranyl, dioxolanyl, substituted dioxolanyl, tetrahydropyrrolyl,piperidinyl, morpholinyl, tetrahydropyranyl, thiophenyl,tetrahydrothiophenyl, sulfolanyl, tetrahydroisoxazolidinyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazole, pyrydyl, substitutedpyridyl, quinolyl, substituted quinolyl, phenyl, substituted phenyl,—CH₂—OCH₃, —(CH₂)₂—OCH₃, and —(CH₂)₃—OCH₃.

According to some embodiments, when R¹ is substituted cyclopropyl, thecyclopropyl ring is substituted with 1 or 2 substituents selected from—OH, —CH₃, —OH, —C(═O)NH₂, —NH₂, —CH₃, —CN, and —CF₃.

According to some embodiments, when R¹ is tetrahydrofuranyl, it istetrahydro-furan-2-yl or tetrahydrofuran-3-yl. According to someembodiments, when R¹ is substituted tetrahydrofuranyl, it is2-methyltetrahydrofuran-2-yl, 5-methyltetrahydrofuran-2-yl,2,5-dimethyltetrahydrofuran-2-yl or tetrahydrofuran-4-one-2-yl,4,4-difluorotetrahydrofuran-2-yl.

According to some embodiments, when R¹ is furanyl, it is 2-furanyl or3-furanyl. According to some embodiments, when R¹ is substituted furanylit is 2-methylfuran-2-yl, 5-methylfuran-2-yl, or 2,5-dimethylfuran-2-yl.

According to some embodiments, when R¹ is dioxolanyl, it is1,3-dioxolan-2-yl. According to some embodiments, when R¹ is substituteddioxolanyl it is 2-methyl-1,3-dioxolan-2-yl.

According to some embodiments, when R¹ is tetrahydroisoxazolidine, it istetra-hydroisoxazolidin-2-yl. According to some embodiments, when R¹ istetrahydropyrrolyl, it is tetrahydropyrrol-1-yl. According to someembodiments, when R¹ is morpholinyl, it is morpholin-1-yl. According tosome embodiments, when R¹ is piperidinyl, it is piperidin-1-yl.According to some embodiments, when R¹ is furanyl, it is 2-furanyl or3-furanyl. According to some embodiments, when R¹ is thiophenyl, it is2-thiophenyl or 2-thiophenyl. According to some embodiments, when R¹ istetrahydrothiophenyl, it is 2-tetrahydrothiophenyl or2-tetrahydrothiophenyl. According to some embodiments, when R¹ issulfolanyl, it is sulfolan-2-yl or sulfolan-3-yl. According to someembodiments, when R¹ is oxazolyl, it is oxazol-1-yl, oxazol-2-one-1-yl,oxazol-2-yl or oxazol-5-yl. According to some embodiments, when R¹ isisoxazolyl, it is isoxazol-1-yl, isoxazol-3-yl or isoxazol-5-yl.According to some embodiments, when R¹ is imidazolyl, it isimidazol-2-yl or imidazol-5-yl. According to some embodiments, when R¹is thiazolyl, it is thiazol-2-yl or thiazol-5-yl. According to someembodiments, when R¹ is isothiazolyl, it is isothiazol-3-yl orisothiazol-5-yl. According to some embodiments, when R¹ is pyridyl, itis 2-pyridyl, 3-pyridyl, or 4-pyridyl. According to some embodiments,when R¹ is substituted quinolyl, it is quinolin-1-yl, quinolin-2-yl orquinolin-3-yl. According to some embodiments, when R¹ is substitutedphenyl, it is 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, or2,5-dimethylphenyl. According to some embodiments, R¹ is selected fromthe moieties depicted in Table 1 and Table 1a (infra).

According to some embodiments, X is selected from —O—, —S—, —SO—, and—SO₂—. According to some embodiments, X is selected from —O—, —S— and—SO₂—. According to some embodiments, X is selected from —O— and —S—.According to some embodiments, X is —O—. According to some embodiments,X is —S—. According to some embodiments, X is —SO—. According to someembodiments, X is —SO₂—. According to some embodiments, X is —NR⁹—.

According to some embodiments, R⁹ is —(C₁-C₆) alkyl. According to someembodiments, the R⁹ group can optionally be structurally connected tothe R⁴ group to form a 5 to 7 membered heterocyclyl ring. According tosome embodiments, the R⁹ group can optionally be structurally connectedto the R⁴ group to form a 5-membered heterocyclyl ring. According tosome embodiments, the R⁹ group can optionally be structurally connectedto the R⁴ group to form a 6-membered heterocyclyl ring. According tosome embodiments, the R⁹ group can optionally be structurally connectedto the R⁴ group to form a 7-membered heterocyclyl ring.

According to some embodiments, R⁴ is —F or —H. According to someembodiments, R⁴ is —H.

According to some embodiments, R⁵ is selected from —H, —C₁-C₆ alkyl,—C₃-C₆ cycloalkyl, and halogen. According to some embodiments, R⁵ is —H.

According to some embodiments, each R¹² is independently selected from—H, halogen, —(C₁-C₆) alkyl, —(C₃-C₆) cycloalkyl, 5-6 memberedheterocyclyl, —OH, —O(C₁-C₆) alkyl, —O(CH₂)_(p)-(5-6 memberedheterocyclyl), —O(CH₂)_(r)—O(C₁-C₆) alkyl, —NH₂, —CN, —NH(C₁-C₆) alkyl,—N(C₁-C₆ alkyl)₂, —NH(CH₂)_(r)—O(C₁-C₆) alkyl, —NH(CH₂)_(r)—N(C₁-C₆alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl, and —C(═O)N(C₁-C₆ alkyl)₂.

According to some embodiments, each R¹² is independently selected from—H, —Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂,—O(CH₂)₂(pyrrolidin-1-yl), —O(CH₂)₃(pyrrolidin-1-yl),—O(CH₂)₂(morpholin-1-yl), —O(CH₂)₃(morpholin-1-yl),—O(CH₂)₂(piperidin-1-yl), —O(CH₂)₃(piperidin-1-yl),—O(CH₂)₂(N-methylpiperazin-1-yl), —O(CH₂)₃(N-methylpiperazin-1-yl),—O(CH₂)₂—OCH₃, —O(CH₂)₃—OCH₃, —O(CH₂)₂—N(CH₃)₂, —O(CH₂)₃—N(CH₃)₂, —NH₂,NHCH₃, N(CH₃)₂, N-methylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-1-yl,piperidin-1-yl, —CF₃, —OCF₃, cyclopropyl, —OH, —C(═O)NH₂, —NH(CH₂)₂pyrrolidin-1-yl, —NH(CH₂)₂N(CH₃)₂, —NH(CH₂)₂OCH₃ and —CN.

According to some embodiments, R⁶ is:

wherein 1 or 2 of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are N, and the remainderof Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹². According to someembodiments, one of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ is N, and theremainder of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹². According to someembodiments, Q² is N, and the remainder of Q¹, Q³, Q⁴, Q⁵, Q⁶ and Q⁷ areC—R¹². According to some embodiments, Q⁶ is N, and Q¹, Q², Q³, Q⁴, Q⁵and Q⁷ are C—R¹². According to some embodiments, Q⁶ is N; Q², Q³, Q⁴, Q⁵and Q⁷ are CH, and Q¹ is C—R¹², wherein —R¹² is other than —H. Accordingto some embodiments, Q⁶ is N; Q², Q³, Q⁴, Q⁵ and Q⁷ are CH, and Q¹ isC—R¹², wherein each —R¹² is independently selected from halogen,—(C₁-C₆) alkyl, —(C₃-C₆) cycloalkyl, 5-6 membered heterocyclyl, —OH,—O(C₁-C₆) alkyl, —O(CH₂)_(r)-(5-6 membered heterocyclyl),—O(CH₂)_(r)—O(C₁-C₆) alkyl, —NH₂, —CN,

—NH(C₁-C₆) alkyl, —N(C₁-C₆ alkyl)₂, —NH(CH₂)_(r)—O(C₁-C₆) alkyl,—NH(CH₂)_(r)—N(C₁-C₆ alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl, and—C(═O)N(C₁-C₆ alkyl)₂; wherein r is an integer selected independentlyfrom 1, 2, 3, and 4.

According to some embodiments, R⁷ is selected from —H, —(C₁-C₇)hydrocarbyl, substituted —(C₁-C₇) hydrocarbyl, —C(═O)R⁸, and —(C₁-C₆)heteroalkyl.

Another aspect of this application is directed to compounds of FormulaIV:

and salts thereof, e.g., pharmaceutically acceptable salts thereof,wherein:

R¹ is selected from —(C₁-C₁₀) hydrocarbyl, substituted —(C₁-C₁₀)hydrocarbyl, 3-7 membered heterocyclyl, substituted 3-7 memberedheterocyclyl, —(C₆-C₁₀) aryl, substituted —(C₆-C₁₀) aryl, 5-6 memberedheteroaryl, substituted 5-6 membered heteroaryl, —NR⁷R⁸, —N(OR⁸)R⁷,—N(SR⁸)R⁷, —SR⁷, —C(═O)—(C₁-C₆) alkyl, and —(C₁-C₆) heteroalkyl;

W¹ is CH or C—R¹⁰;

R⁷ is selected from —H, —(C₁-C₇) hydrocarbyl, substituted —(C₁-C₇)hydrocarbyl, —C(═O)—(C₁-C₇) hydrocarbyl, —(C₁-C₆) heteroalkyl, 6membered aryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl;

R⁸ is selected from —H, and —(C₁-C₆) alkyl, wherein R⁷ can optionally bestructurally connected to R⁸ to form a 5 to 7 membered heterocyclylring;

R¹⁰ is selected from —F, —Cl, —CN, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl,—OH, —O(C₁-C₆)alkyl, NH₂, —NH(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂,—C(═O)(C₁-C₆)alkyl, —C(═O)—(C₃-C₆) cycloalkyl, —C(═O)NH₂, —CF₃; and

each R¹² is independently selected from —H, halogen, —(C₁-C₆) alkyl,—(C₁-C₃) haloalkyl, —O(C₁-C₃) haloalkyl, —(C₃-C₆) cycloalkyl, 5-6membered heterocyclyl, —OH, —O(C₁-C₆) alkyl, —O(CH₂)_(r)-(5-6 memberedheterocyclyl), —O(CH₂)_(r)-O(C₁-C₆) alkyl, —O(CH₂)_(r)—N(C₁-C₆ alkyl)₂,—NH₂, —CN, —NH(C₁-C₆) alkyl, —N(C₁-C₆ alkyl)₂, —NH(CH₂)_(r)O(C₁-C₆)alkyl, —NH(CH₂)_(r)—N(C₁-C₆ alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl,and —C(═O)N(C₁-C₆ alkyl)₂; wherein R¹² may be at any position on thequinoline ring to which it is attached, and wherein r is an integerindependently selected from 1, 2, 3 and 4; and q is an integer selectedfrom 0, 1, 2 and 3. According to some embodiments, q is 0 or 1.According to some embodiments, q is 1. It will be understood that avalue of 0 for q is the equivalent of all R¹² moieties being —H.

According to some embodiments, R¹ is selected from —(C₁-C₁₀)hydrocarbyl, substituted —(C₁-C₁₀) hydrocarbyl, 3-7 memberedheterocyclyl, substituted 3-7 membered heterocyclyl, —(C₆-C₁₀) aryl,substituted —(C₆-C₁₀) aryl, 5-6 membered heteroaryl, substituted 5-6membered heteroaryl, —NR⁷R⁸, —N(OR⁸)R⁷, —C(═O)—(C₁-C₆) alkyl, and—(C₁-C₆) heteroalkyl;

According to some embodiments, R¹ is selected from —NR⁷R⁸—SR⁷, —N(SR⁸)R⁷and —N(OR⁸)R⁷. According to some embodiments, R¹ is selected from —NR⁷R⁸and —N(OR⁸)R⁷.

According to some embodiments, W¹ is CH.

According to some embodiments, R⁷ is selected from —H, —(C₁-C₇)hydrocarbyl, substituted —(C₁-C₇) hydrocarbyl, —C(═O)—(C₁-C₇)hydrocarbyl, and —(C₁-C₆) heteroalkyl.

According to some embodiments, R⁷ is selected from —H, —(C₁-C₆)alkyl,substituted —(C₁-C₆) alkyl, —C(═O)—(C₁-C₆) alkyl, and —(C₁-C₆)heteroalkyl;

According to some embodiments, R⁸ is selected from —H, and —(C₁-C₆)alkyl.

According to some embodiments, each R¹² is independently selected from—H, halogen, —(C₁-C₆) alkyl, —(C₃-C₆) cycloalkyl, 5-6 memberedheterocyclyl, —OH, —O(C₁-C₆) alkyl, —O(CH₂)_(r)-(5-6 memberedheterocyclyl), —O(CH₂)_(r)-O(C₁-C₆) alkyl, —NH₂, —CN, —NH(C₁-C₆) alkyl,—N(C₁-C₆ alkyl)₂, —NH(CH₂)_(r)—O(C₁-C₆) alkyl, —NH(CH₂)_(r)—N(C₁-C₆alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl and —C(═O)N(C₁-C₆ alkyl)₂.

According to some embodiments, each R¹² is independently selected from—H, halogen, —(C₁-C₆) alkyl, —(C₃-C₆) cycloalkyl, 5-6 memberedheterocyclyl, —OH, —O(C₁-C₆) alkyl, —CN, —NH(C₁-C₆) alkyl, —N(C₁-C₆alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl, and —C(═O)N(C₁-C₆ alkyl)₂.

Another aspect of this application is directed to compounds of FormulaV:

and salts thereof, e.g., pharmaceutically acceptable salts thereof,wherein:

R^(1b) is selected from —NR⁷R⁸ and —N(OR⁸)R⁷;

a and b are independently selected from 0 and 1;

each R² is independently selected from —H and —(C₁-C₄) alkyl;

each R³ is independently selected from —H and —(C₁-C₄) alkyl

R⁴ is selected from —H, —(C₁-C₆) alkyl, ═O, —OH, —O(C₁-C₆) alkyl,halogen, and —CN; wherein one of the R³ groups can optionally bestructurally connected to one of the R² groups to form an alkylenebridge to produce a bicyclic ring; or

one of the R³ groups can optionally be structurally connected to the R¹group to form a 5 to 7 membered heterocyclyl ring fused to the 1-2 faceof the piperidine ring; or

one of the R³ groups can optionally be structurally connected to the R⁴group to form a 5-7 membered carbocyclic or heterocyclic ring fused tothe 2-3 face of the piperidine ring;

signifies that the designated bond is a carbon-carbon single bond or acarbon-carbon double bond;

X is selected from —O—, —S—, —SO—, —SO₂—, and —NR⁹—;

W¹, W² and W³ are independently selected from N, CH, and C—R¹⁰; providedthat W² and W³ are not both N;

R⁵ is selected from —H, —C₁-C₇ hydrocarbyl, —C₃-C₆ heterocyclyl;halogen, —(C₁-C₃) haloalkyl, —OR^(7a), —CN, —NR^(7a)R^(8a),—O(CH₂)_(n)NR^(7a)R^(8a), —O(CH₂)_(n)OR^(8a),—NR^(8a)(CH₂)_(n)NR^(7a)R^(8a), —NR^(8a)(CH₂)_(n)OR^(8a),—C(═O)NR^(7a)R^(8a), —C(═O)OR^(7a), 5-6 membered heteroaryl, andsubstituted 5-6 membered heteroaryl;

n is an integer selected from 1, 2, 3, and 4;

R⁶ is selected from 6-membered heteroaryl, substituted 6-memberedheteroaryl, 9-10 membered bicyclic heteroaryl, and substituted 9-10membered bicyclic heteroaryl;

R⁷ is selected from —H, —(C₁-C₇) hydrocarbyl, substituted —(C₁-C₇)hydrocarbyl, —C(═O)R⁸, and —(C₁-C₆) heteroalkyl;

R⁸ is selected from —H, and —(C₁-C₆) alkyl, wherein R⁷ can optionally bestructurally connected to R⁸ to form a 5 to 7 membered heterocyclylring;

R^(7a) is selected from —H, —(C₁-C₇) hydrocarbyl, substituted —(C₁-C₇)hydrocarbyl, —C(═O)R⁸, and —(C₁-C₆) heteroalkyl;

R^(8a) is selected from —H, and —(C₁-C₆) alkyl, wherein R^(7a) canoptionally be structurally connected to R^(8a) to form a 5 to 7 memberedheterocyclyl ring;

R⁹ is selected from —(C₁-C₇) hydrocarbyl, wherein R⁹ can optionally bestructurally connected to R⁴ to form a 5 to 7 membered heterocyclylring;

each R¹⁰ is independently selected from —(C₁-C₇) hydrocarbyl,substituted —(C₁-C₇) hydrocarbyl, halogen, —C(═O)—(C₁-C₇) hydrocarbyl,—C(═O)NH₂, —C(═O)NH—(C₁-C₇) hydrocarbyl, —C(═O)N(C₁-C₇ hydrocarbyl)₂,—OH, —O(C₁-C₇) hydrocarbyl, substituted —O(C₁-C₇) hydrocarbyl, —(C₃-C₆)heterocyclyl, substituted —(C₃-C₆) heterocyclyl —CN, —NH₂,—NH(C₁-C₆)alkyl, —N(C₁-C₆ alkyl)₂, —NH(CH₂)_(m)—R¹¹, —N(C₁-C₆alkyl)(CH₂)_(m)—R¹¹, —O—(CH₂)_(m)—R¹¹, and —(C₁-C₆) heteroalkyl; m is aninteger selected independently from 1, 2, 3, and 4; and

R¹¹ is selected from —O—(C₁-C₆)alkyl, —N(C₁-C₆ alkyl)₂,—(C₃-C₆)heterocyclyl and substituted —(C₃-C₆) heterocyclyl.

According to some embodiments, a and b are both 1.

According to some embodiments, R² is —H.

According to some embodiments, R³ is —H.

According to some embodiments, R⁴ is selected from —H, —(C₁-C₆) alkyland halogen.

According to some embodiments, one of the R³ groups is structurallyconnected to one of the R² groups to form a —CH₂—CH₂— bridge to producea bicyclic ring; for example:

According to some embodiments, one of the R³ groups is structurallyconnected to the R^(1b) group to form a 5- or 6-membered heterocyclicring fused to the 1-2 face of the piperidine ring; for example:

According to some embodiments, one of the R³ groups is structurallyconnected to the R⁴ group to form a 5-membered carbocyclic orheterocyclic ring fused to the 2-3 face of the piperidine ring; forexample:

According to some embodiments,

is a carbon-carbon single bond.

According to some embodiments, X is —O—.

According to some embodiments, W¹, W² and W³ are independently selectedfrom CH, and C—R¹⁰. According to some embodiments, W¹, W² and W³ are CH.

According to some embodiments, R⁵ is selected from —H, —C₁-C₆ alkyl, andhalogen. According to some embodiments, R⁵ is —H.

According to some embodiments, R⁹ is —(C₁-C₆) alkyl.

According to some embodiments, R⁶ is selected from 9-10 memberedbicyclic heteroaryl, and substituted 9-10 membered bicyclic heteroaryl;provided that, when R⁶ is a 9-membered bicyclic heteroaryl or asubstituted 9-membered bicyclic heteroaryl, the point of attachment ofR⁶ to the aromatic ring containing W¹, W² and W³ is on a 6-membered ringportion of the 9-membered bicyclic heteroaryl or substituted 9-memberedbicyclic heteroaryl. According to some embodiments, R⁶ is selected from:

wherein, when R⁶ is (i), Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are independentlyselected from N and C—R¹², provided that 1, 2 or 3 of Q¹, Q², Q³, Q⁴,Q⁵, Q⁶ and Q⁷ are N, and the remainder of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷are C—R¹²;

when R⁶ is (ii), Q^(1a), Q^(2a), Q^(3a), Q^(4a), Q^(5a), Q^(6a) and Q⁷aare independently selected from N and C—R¹², provided that 1, 2 or 3 ofQ^(1a), Q²a, Q³a, Q^(4a), Q^(5a), Q^(6a) and Q⁷a are N, and theremainder of Q^(1a), Q²a, Q³a, Q⁴a, Q⁵a, Q⁶a and Q⁷a are C—R¹²;

when R⁶ is (iii), Q⁸ is selected from O, S, and N—R^(12n), Q⁹, Q¹⁰ andQ¹¹ are independently selected from N and C—R¹², provided that 1 or 2 ofQ⁹, Q¹⁰ and Q¹¹ are N, and the remainder of Q⁹, Q¹⁰ and Q¹¹ are C—R¹²;

when R⁶ is (iv), Q^(8a) is selected from O, S, and N—R^(12n), Q^(9a),Q^(10a) and Q^(11a) are independently selected from N and C—R¹²,provided that 1 or 2 of Q⁹, Q¹⁰ and Q¹¹ are N, and the remainder of Q⁹,Q¹⁰ and Q¹¹ are C—R¹²;

when R⁶ is (v), Q¹², Q¹³ and Q¹⁴ are independently selected from N andC—R¹²; and

when R⁶ is (vi), Q^(12a), Q^(13a) and Q^(14a) are independently selectedfrom N and C—R¹²;

when R⁶ is (vii), Q¹⁵ is selected from N—R^(12n) and C—R¹² and Q¹⁶ isselected from N and C—R¹²; provided that one of Q¹⁵ and Q¹⁶ are not bothC—R¹²;

and wherein each R¹² is independently selected from —H, halogen,—(C₁-C₆) alkyl, —(C₃-C₆) cycloalkyl, —(C₁-C₃) haloalkyl, —O(C₁-C₃)haloalkyl, 5-6 membered heterocyclyl, —OH, —O(C₁-C₆) alkyl,—O(CH₂)_(r)-(5-6 membered heterocyclyl), —O(CH₂)_(r)—O(C₁-C₆) alkyl,—O(CH₂)_(r)—N(C₁-C₆ alkyl)₂, —NH₂, —CN, —NH(C₁-C₆) alkyl,

—N(C₁-C₆ alkyl)₂, —NH(CH₂)_(r)—O(C₁-C₆) alkyl, —NH(CH₂)_(r)—N(C₁-C₆alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl, and —C(═O)N(C₁-C₆ alkyl)₂;wherein r is an integer selected independently from 1, 2, 3, and 4; and

each R^(12n) is selected from —H, —(C₁-C₇) hydrocarbyl and substituted—(C₁-C₇) hydrocarbyl.

It will be understood that the ring carbon ring atoms in (i), (ii),(iii), (iv), (v), (vi) and (vii) above (i.e., ring atoms which are notdesignated as N or Q) may optionally be substituted. According to someembodiments, none of these ring carbon ring atoms are substituted.According to some embodiments one or two of these ring carbon ring atomsis substituted with a substituent selected from —OH,

—(C₁-C₃) alkyl, —O(C₁-C₃)alkyl and halogen. According to someembodiments, one of these ring carbon ring atoms is substituted with asubstituent selected from —OH,—CH₃, —OCH₃, —F and —Cl.

According to some embodiments, each R¹² is independently selected from—H, halogen, —(C₁-C₆) alkyl, —(C₃-C₆) cycloalkyl, 5-6 memberedheterocyclyl, —OH, —O(C₁-C₆) alkyl, —O(CH₂)_(r)-(5-6 memberedheterocyclyl), —O(CH₂)_(r)—O(C₁-C₆) alkyl, —NH₂, —CN, —NH(C₁-C₆) alkyl,—N(C₁-C₆ alkyl)₂, —NH(CH₂)_(r)—O(C₁-C₆) alkyl, —NH(CH₂)_(r)—N(C₁-C₆alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl, and —C(═O)N(C₁-C₆ alkyl)₂.

According to some embodiments, each R¹² is independently selected from—H, —Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, —CF₃, —OCF₃,—O(CH₂)₂(pyrrolidin-1-yl), —O(CH₂)₃(pyrrolidin-1-yl),—O(CH₂)₂(morpholin-1-yl), —O(CH₂)₃(morpholin-1-yl),—O(CH₂)₂(piperidin-1-yl), —O(CH₂)₃(piperidin-1-yl),—O(CH₂)₂(N-methylpiperazin-1-yl), —O(CH₂)₃(N-methylpiperazin-1-yl),—O(CH₂)₂—OCH₃, —O(CH₂)₃—OCH₃, —O(CH₂)₂—N(CH₃)₂, —O(CH₂)₃—N(CH₃)₂, —NH₂,NHCH₃, N(CH₃)₂, N-methylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-1-yl,and piperidin-1-yl.

According to some embodiments, each R¹² is independently selected from—H, —Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂,—O(CH₂)₂(pyrrolidin-1-yl), —O(CH₂)₃(pyrrolidin-1-yl),—O(CH₂)₂(morpholin-1-yl), —O(CH₂)₃(morpholin-1-yl),—O(CH₂)₂(piperidin-1-yl), —O(CH₂)₃(piperidin-1-yl),—O(CH₂)₂(N-methylpiperazin-1-yl), —O(CH₂)₃(N-methylpiperazin-1-yl),—O(CH₂)₂—OCH₃, —O(CH₂)₃—OCH₃, —O(CH₂)₂—N(CH₃)₂, —O(CH₂)₃—N(CH₃)₂, —NH₂,NHCH₃, N(CH₃)₂, N-methylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-1-yl,and piperidin-1-yl.

According to some embodiments, R^(12n) is selected from —H, benzyl and—C₁-C₆ alkyl.

According to some embodiments, R⁶ is selected from the aromatic ringsystems depicted in Table 1b (infra).

According to some embodiments, R⁶ is:

wherein 1 or 2 of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are N, and the remainderof Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹². According to someembodiments, when R⁶ is (i), one of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ is N,and the remainder of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹². Accordingto some embodiments, when R⁶ is (i), Q² is N, and the remainder of Q¹,Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹². According to some embodiments, when R⁶is (i), Q⁶ is N, and Q¹, Q², Q³, Q⁵, Q⁵ and Q⁷ are C—R¹². According tosome embodiments, when R⁶ is (i), Q⁶ is N, Q², Q³, Q⁵, Q⁵ and Q⁷ are CH,and Q¹ is C—R¹², wherein —R¹² is other than —H.

According to some embodiments, R⁶ is:

wherein one of Q² and Q⁶ is N, and the other of Q² and Q⁶ is C—R¹², andq is an integer selected from 0, 1, 2 and 3. According to someembodiments of i², Q² is N, and Q⁶ is C—R¹². According to someembodiments, Q⁶ is N, and Q² is C—R¹². According to some embodiments, qis selected from 0, 1 and 2. According to some embodiments of i², q is 0or 1. It will be understood that a q value of 0 is the equivalent ofdesignating all R¹² that are bonded to the i² bicyclic heteroaryl atother than Q² and Q⁶ as being —H.

According to some embodiments of i², each R¹² is independently selectedfrom —H, —Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂,—O(CH₂)₂(pyrrolidin-1-yl), —O(CH₂)₃(pyrrolidin-1-yl),—O(CH₂)₂(morpholin-1-yl), —O(CH₂)₃(morpholin-1-yl),—O(CH₂)₂(piperidin-1-yl), —O(CH₂)₃(piperidin-1-yl),—O(CH₂)₂(N-methylpiperazin-1-yl), —O(CH₂)₃(N-methylpiperazin-1-yl),—O(CH₂)₂—OCH₃, —O(CH₂)₃—OCH₃, —O(CH₂)₂—N(CH₃)₂, —O(CH₂)₃—N(CH₃)₂, —NH₂,NHCH₃, N(CH₃)₂, N-methylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-1-yl,and piperidin-1-yl.

According to some embodiments of i², each R^(12n) is independentlyselected from —H, benzyl and —C₁-C₆ alkyl.

According to some embodiments, R⁶ is:

wherein one or two of Q², Q⁴ and Q⁶ is N, and the remainder of Q², Q⁴and Q⁶ are C—R¹², and q is an integer selected from 0, 1, 2 and 3.

According to some embodiments of i³, each R¹² is independently selectedfrom —H, halogen, —(C₁-C₆) alkyl, —(C₃-C₆) cycloalkyl, 5-6 memberedheterocyclyl, —OH, —O(C₁-C₆) alkyl, —O(CH₂)_(r)-(5-6 memberedheterocyclyl), —O(CH₂)_(r)—O(C₁-C₆) alkyl, —NH₂, —CN, —NH(C₁-C₆) alkyl,—N(C₁-C₆ alkyl)₂, —NH(CH₂)_(r)—O(C₁-C₆) alkyl, —NH(CH₂)_(r)—N(C₁-C₆alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl, and —C(═O)N(C₁-C₆ alkyl)₂;wherein r is an integer selected from 1, 2, 3 and 4; or a salt thereof.

According to some embodiments of i³, each R¹² is independently selectedfrom —H, —Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂,—O(CH₂)₂(pyrrolidin-1-yl), —O(CH₂)₃(pyrrolidin-1-yl),—O(CH₂)₂(morpholin-1-yl), —O(CH₂)₃(morpholin-1-yl),—O(CH₂)₂(piperidin-1-yl), —O(CH₂)₃(piperidin-1-yl),—O(CH₂)₂(N-methylpiperazin-1-yl), —O(CH₂)₃(N-methylpiperazin-1-yl),—O(CH₂)₂—OCH₃, —O(CH₂)₃—OCH₃, —O(CH₂)₂—N(CH₃)₂, —O(CH₂)₃—N(CH₃)₂, —NH₂,NHCH₃, N(CH₃)₂, N-methylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-1-yl,and piperidin-1-yl. According to some embodiments of i³, each R¹² isindependently selected from —H, —Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, and—OCH₂CH₃.

According to some embodiments of i³, q is 0, 1 or 2. According to someembodiments, q is 0 or 1. It will be understood that a q value of 0 isthe equivalent of designating all R¹² that are bonded to the bicyclicheteroaryl moiety at other than Q², Q⁴ or Q⁶ as being —H.

According to some embodiments of i³, Q² is N, and Q⁴ and Q⁶ are C—R¹².According to some embodiments of i³, Q⁶ is N, and Q² and Q⁴ are C—R¹².According to some embodiments of i³, Q⁴ is N, and Q² and Q⁶ are C—R¹².According to some embodiments of i³, Q² is C—R¹², and Q⁴ and Q⁶ are N.According to some embodiments of i³, Q⁶ is C—R¹², and Q² and Q⁴ are N.According to some embodiments of i³, Q⁴ is C—R¹², and Q² and Q⁶ are N.

According to some embodiments, R⁷ is selected from —H, —(C₁-C₆) alkyl,substituted —(C₁-C₆)alkyl, —(C₃-C₆) cycloalkyl, substituted—(C₃-C₆)cycloalkyl, —(C₂-C₆) alkenyl, substituted —(C₂-C₆)alkenyl,benzyl, substituted benzyl, —C(═O)R⁸, and —(C₁-C₆) heteroalkyl.According to some embodiments, R⁷ is selected from —H, and —(C₁-C₆)alkyl.

According to some embodiments, R^(7a) is selected from —H, —(C₁-C₆)alkyl, substituted —(C₁-C₆)alkyl, —(C₃-C₆) cycloalkyl, substituted—(C₃-C₆)cycloalkyl, —(C₂-C₆) alkenyl, substituted —(C₂-C₆)alkenyl,benzyl, substituted benzyl, —C(═O)R⁸, and —(C₁-C₆) heteroalkyl.According to some embodiments, R^(7a) is selected from —H and —(C₁-C₆)alkyl.

According to some embodiments, R⁸ is selected from —H, and —(C₁-C₆)alkyl. According to some embodiments, R⁸ is selected from —H, —CH₃ and—CH₂CH₃.

According to some embodiments, R^(8a) is selected from —H, and —(C₁-C₆)alkyl. According to some embodiments, R^(8a) is selected from —H, —CH₃and —CH₂CH₃.

Another aspect of this application is directed to compounds of FormulaV(a), (which is a subset of compounds according to Formula V):

and salts thereof, e.g., pharmaceutically acceptable salts thereof,wherein:

R^(1b) is selected from —NR⁷R⁸ and —N(OR⁸)R⁷;

R⁴ is selected from —H, —(C₁-C₆) alkyl, ═O, —OH, —O(C₁-C₆) alkyl,halogen and —CN;

X is selected from —O— and —S—;

R⁵ is selected from —H, —C₁-C₇ hydrocarbyl, —C₃-C₆ heterocyclyl;halogen, —(C₁-C₃) haloalkyl, —OR^(7a), —CN, —NR^(7a)R^(8a),—O(CH₂)_(n)NR^(7a)R^(8a), —O(CH₂)_(n)OR^(8a),—NR^(8a)(CH₂)_(n)NR^(7a)R^(8a), —NR^(8a)(CH₂)_(n)OR^(8a),—C(═O)NR^(7a)R^(8a), —C(═O)OR^(7a), 5-6 membered heteroaryl andsubstituted 5-6 membered heteroaryl;

n is an integer selected from 1, 2, 3, and 4;

R⁷ is selected from —H, —(C₁-C₇) hydrocarbyl, substituted —(C₁-C₇)hydrocarbyl, —C(═O)R⁸, and —(C₁-C₆) heteroalkyl;

R⁸ is selected from —H, and —(C₁-C₆) alkyl, wherein R⁷ can optionally bestructurally connected to R⁸ to form a 5 to 7 membered heterocyclylring;

R^(7a) is selected from —H, —(C₁-C₇) hydrocarbyl, substituted —(C₁-C₇)hydrocarbyl, —C(═O)R⁸, and —(C₁-C₆) heteroalkyl;

R^(8a) is selected from —H, and —(C₁-C₆) alkyl, wherein R^(7a) canoptionally be structurally connected to R^(8a) to form a 5 to 7 memberedheterocyclyl ring;

Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are independently selected from N andC—R¹², provided that 1, 2 or 3 of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are N,and the remainder of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹².

each R¹² is independently selected from —H, halogen, —(C₁-C₆) alkyl,—(C₁-C₃) haloalkyl, —O(C₁-C₃) haloalkyl, —(C₃-C₆) cycloalkyl, 5-6membered heterocyclyl, —OH, —O(C₁-C₆) alkyl, —O(CH₂)_(r)-(5-6 memberedheterocyclyl), —O(CH₂)_(r)—O(C₁-C₆) alkyl, —NH₂, —O(CH₂)_(r)—N(C₁-C₆alkyl)₂, —CN, —NH(C₁-C₆) alkyl, —N(C₁-C₆ alkyl)₂, —NH(CH₂)_(r)—O(C₁-C₆)alkyl, —NH(CH₂)_(r)—N(C₁-C₆ alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl,and —C(═O)N(C₁-C₆ alkyl)₂; and r is an integer selected independentlyfrom 1, 2, 3, and 4.

According to some embodiments, R⁴ is selected from —H, —(C₁-C₆) alkyland halogen.

According to some embodiments, X is —O—.

According to some embodiments, R⁵ is selected from —H, —C₁-C₆ alkyl, andhalogen. According to some embodiments, R⁵ is —H.

According to some embodiments, each R¹² is independently selected from—H, halogen, —(C₁-C₆) alkyl, —(C₃-C₆) cycloalkyl, 5-6 memberedheterocyclyl, —OH, —O(C₁-C₆) alkyl, —O(CH₂)_(r)-(5-6 memberedheterocyclyl), —O(CH₂)_(r)—O(C₁-C₆) alkyl, —NH₂, —CN, —NH(C₁-C₆) alkyl,—N(C₁-C₆ alkyl)₂, —NH(CH₂)_(r)—O(C₁-C₆) alkyl, —NH(CH₂)_(r)—N(C₁-C₆alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl, and —C(═O)N(C₁-C₆ alkyl)₂.

According to some embodiments, each R¹² is independently selected from—Cl, —F, —CH₃, —CH₂CH₃, —CF₃, —OCF₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂,—O(CH₂)₂(pyrrolidin-1-yl), —O(CH₂)₃(pyrrolidin-1-yl),—O(CH₂)₂(morpholin-1-yl), —O(CH₂)₃(morpholin-1-yl),—O(CH₂)₂(piperidin-1-yl), —O(CH₂)₃(piperidin-1-yl),—O(CH₂)₂(N-methylpiperazin-1-yl), —O(CH₂)₃(N-methylpiperazin-1-yl),—O(CH₂)₂—OCH₃, —O(CH₂)₃—OCH₃, —O(CH₂)₂—N(CH₃)₂, —O(CH₂)₃—N(CH₃)₂, —NH₂,NHCH₃, N(CH₃)₂, N-methylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-1-yl,and piperidin-1-yl.

According to some embodiments, each R¹² is independently selected from—Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂,—O(CH₂)₂(pyrrolidin-1-yl), —O(CH₂)₃(pyrrolidin-1-yl),—O(CH₂)₂(morpholin-1-yl), —O(CH₂)₃(morpholin-1-yl),—O(CH₂)₂(piperidin-1-yl), —O(CH₂)₃(piperidin-1-yl),—O(CH₂)₂(N-methylpiperazin-1-yl), —O(CH₂)₃(N-methylpiperazin-1-yl),—O(CH₂)₂—OCH₃, —O(CH₂)₃—OCH₃, —O(CH₂)₂—N(CH₃)₂, —O(CH₂)₃—N(CH₃)₂, —NH₂,NHCH₃, N(CH₃)₂, N-methylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-1-yl,and piperidin-1-yl.

Compounds according to Formula I may include for example:1-[4-(4-isoquinolin-6-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;2-methyl-1-[4-(4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-propan-1-one;4-(2-fluoro-4-quinolin-3-yl-phenox)piperidine-1-carboxylic acidtert-butyl ester;1-[4-(2-fluoro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]propan-1-one;1-[4-(2-fluoro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one;1-[4-(4-benzofuran-5-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(4-benzofuran-5-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one;1-[4-(4-naphthalen-2-yl-phenoxy)-piperidin-1-yl]-propan-1-one;2-methyl-1-[4-(4-naphthalen-2-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(4-1,5-naphthyridin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;2-methyl-1-[4-(4-1,5-naphthyridin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(4-1,5-naphthyridin-3-yl-phenoxy)-piperidin-1-yl]-methanone;4-(2-fluoro-4-quinolin-3-yl-phenoxy)-piperidine-1-carboxylic acid methylester;1-{4-[4-(2-chloro-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(2-chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-cyclopropylmethanone;1-{4-[4-(2-methoxy-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(5,6,7,8-tetrahydroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(5,6,7,8-tetrahydroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(5,6,7,8-tetrahydroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;1-{4-[4-(8-fluoroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-fluoro-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(8-fluoroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(8-fluoro-2-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-fluoro-2-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(8-fluoro-2-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(5-fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(5-fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(5-fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(5-fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclopropyl-{4-[4-(7-methoxy-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;1-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclopropyl-[4-(4-quinolin-2-yl-phenoxy)-piperidin-1-yl]-methanone;1-[4-(4-quinolin-2-yl-phenoxy)-piperidin-1-yl]-propan-1-one;cyclobutyl-[4-(4-quinolin-2-yl-phenoxy)-piperidin-1-yl]-methanone;[4-(4-quinolin-2-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydrofuran-2-yl-methanone;1-[4-(4-isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(4-isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;cyclobutyl-[4-(4-isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;[4-(4-isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(4-chloroquinolin-3-yl)-phenoxy]-piperidin-l-yl}-propan-1-one;{4-[4-(4-chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-cyclopropyl-methanone;{4-[4-(4-chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-cyclobutylmethanone;1-{4-[4-(4-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl})-propan-1-one;1-[4-(4-furo[3,2-b]pyridin-6-yl-phenoxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(4-furo[3,2-b]pyridin-6-yl-phenoxy)-piperidin-1-yl]-methanone;1-{4-[4-(6-methoxy-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(6-methoxy-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(6,7-dimethoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(6,7-dimethoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(8-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(8-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-cyclopropyl-methanone;1-{4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(7-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(7-methyl-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-[4-(4-quinoxalin-2-ylphenoxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(4-quinoxalin-2-yl-phenoxy)-piperidin-1-yl]-methanone;[4-(4-quinoxalin-2-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(S)-tetrahydrofuran-2-yl-methanone;{4-[4-(4-chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propane-1,2-dione;isoxazolidin-2-yl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;[4-(4-isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-isoxazolidin-2-yl-methanone;isoxazolidin-2-yl-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(4-chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-isoxazolidin-2-yl-methanone;{4-[4-(8-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-isoxazolidin-2-yl-methanone;isoxazolidin-2-yl-{4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-{4-[4-(7-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-[4-(4-quinoxalin-2-yl-phenoxy)-piperidin-1-yl]-methanone;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidmethoxyamide;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidmethoxymethyl-amide;4-[4-(4-methyl-quinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidethylamide;4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidmethylamide;4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidethylamide;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidhydroxyamide;N-ethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N,N-dimethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;ethyl 4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate;N-methoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-ethoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-pyrrolidin-1-yl-methanone;N-methyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(1-piperidyl)methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-morpholinomethanone;cyclopropyl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;cyclobutyl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;cyclopentyl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydrofuran-2-yl-methanone;[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-(S)-tetrahydrofuran-2-yl-methanone;2-methoxy-1-[4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-ethanone;[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-(tetrahydropyran-2-yl)-methanone;[4-(4-quinolin-3-yl-phenoxyl)-piperidin-1-yl]-(tetrahydrofuran-3-yl)-methanone;(R)-2-methoxy-1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;(S)-2-methoxy-1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;2-hydroxy-1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-ethanone;[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-(tetrahydropyran-2-yl)-methanone;1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-ethanone;2-methyl-1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;2,2-dimethyl-1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;(2-methyl-1,3-dioxolan-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;2-methanesulfonyl-1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-ethanone;(1,1-dioxidotetrahydrothiophen-2-yl)(4-(4-(quinolin-3-yl)phenoxy)piperidin-1-yl)methanone;(3,3-difluoro-cyclobutyl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;(R)-5-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-dihydrofuran-2-one;(3-methylfuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;(3,5-dimethylfuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;oxazol-2-yl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;isoxazol-3-yl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;isothiazol-3-yl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-(tetrahydrofuran-2-yl)-methanone;phenyl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;(2,5-dimethyl-phenyl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;[3-(1H-imidazol-2-yl)-phenyl]-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;[3-(1H-benzimidazol-2-yl)-phenyl]-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;N-methoxy-4-[4-(8-methoxy-7-quinolyl)phenoxy]piperidine-1-carboxamide;1-[4-(5-quinolin-3-yl-pyridin-2-yloxy)-piperidin-1-yl]-propan-1-one;2-methyl-1-[4-(5-quinolin-3-yl-pyridin-2-yloxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(5-quinolin-3-yl-pyridin-2-yloxy)-piperidin-1-yl]-methanone;1-[4-(5-quinolin-7-yl-pyridin-2-yloxy)-piperidin-1-yl]-propan-1-one;2-methyl-1-[4-(5-quinolin-7-yl-pyridin-2-yloxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(5-quinolin-7-yl-pyridin-2-yloxy)-piperidin-1-yl]-methanone;2-methyl-1-[4-(5-quinolin-3-yl-pyrimidin-2-yloxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(5-quinolin-3-yl-pyrimidin-2-yloxy)-piperidin-1-yl]-methanone;1-[4-(6-quinolin-3-yl-pyridin-3-yloxy)-piperidin-1-yl]-propan-1-one;2-methyl-1-[4-(6-quinolin-3-yl-pyridin-3-yloxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(6-quinolin-3-yl-pyridin-3-yloxy)-piperidin-1-yl]-methanone;1-[4-(5-quinolin-3-yl-pyrimidin-2-yloxy)-piperidin-1-yl]-propan-1-one;1-[4-(6-quinolin-7-yl-pyridin-3-yloxy)-piperidin-1-yl]-propan-1-one;2-methyl-1-[4-(6-quinolin-7-yl-pyridin-3-yloxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(6-quinolin-7-yl-pyridin-3-yloxy)-piperidin-1-yl]-methanone;1-[4-(6-isoquinolin-6-yl-pyridin-3-yloxy)-piperidin-1-yl]-propan-1-one;1-[4-(6-isoquinolin-6-yl-pyridin-3-yloxy)-piperidin-1-yl]-2-methyl-propan-1-one;cyclopropyl-[4-(6-isoquinolin-6-yl-pyridin-3-yloxy)-piperidin-1-yl]-methanone;1-propionyl-piperidine-4-carboxylic acidmethyl-(4-quinolin-7-yl-phenyl)-amide;1-propionyl-piperidine-4-carboxylic acid(4-isoquinolin-6-yl-phenyl)-methyl-amide;oxo-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-acetaldehyde;4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbaldehyde;((2R,3S)/(2S,3R)-3-methyltetrahydrofuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;((2R,3S,5R)/(2S,3R,5S)-3,5-dimethyl-tetrahydrofuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;((2R,3S,5R)/(2S,3R,5S)-3,5-dimethyltetrahydrofuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;1-propionyl-piperidine-4-carboxylic acid(4-isoquinolin-6-yl-phenyl)-methylamide;2-fluoro-4-isoquinolin-6-yl-N-methyl-N-(1-propionyl-piperidin-4-yl)-benzamide;1-{4-[4-(3-trifluoromethyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(3-trifluoromethyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;(R)-tetrahydrofuran-2-yl-{4-[4-(3-trifluoromethyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;3-[4-(1-methanesulfonyl-piperidin-4-yloxy)-phenyl]-quinoline;(4,4-difluorotetrahydro-furan-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;(4,4-difluorotetrahydrofuran-2-yl)-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;(4,4-difluorotetrahydrofuran-2-yl)-{4-[4-(1-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;5-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-dihydrofuran-3-one;1-{4-[4-(8-ethoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-ethoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(8-isopropoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-isopropoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;1-(4-{4-[8-(2-morpholin-4-yl-ethoxy)-quinolin-7-yl]-phenoxy)}-piperidin-1-yl)-propan-1-one;cyclopropyl-(4-{4-[8-(2-morpholin-4-yl-ethoxy)-quinolin-7-yl]-phenoxyl}-piperidin-1-yl)-methanone;1-(4-{4-[8-(2-pyrrolidin-1-yl-ethoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one;cyclopropyl-(4-{4-[8-(2-pyrrolidin-1-yl-ethoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-methanone;1-(4-{4-[8-(3-pyrrolidin-1-yl-propoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one;cyclopropyl-(4-{4-[8-(3-pyrrolidin-1-yl-propoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-methanone;1-[4-[4-[8-[2-(4-methylpiperazin-1-yl)ethoxy]-7-quinolyl]phenoxy]-1-piperidyl]propan-1-one;1-[4-[4-[8-(2-methoxyethoxy)-7-quinolyl]phenoxy]-1-piperidyl]propan-1-one;1-[4-[4-[8-(3-methoxypropoxy)-7-quinolyl]phenoxy]-1-piperidyl]propan-1-one;{4-[4-(8-isopropoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(8-ethoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;(4-{4-[8-(2-morpholin-4-yl-ethoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone;(4-{4-[8-(2-pyrrolidin-1-yl-ethoxy)quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone;(4-{4-[8-(3-pyrrolidin-1-yl-propoxy)-quinolin-7-yl]-phenoxy})-piperidin-1-yl)-(R)-tetrahydrofuran-2-ylmethanone;[4-[4-[8-[2-(4-methylpiperazin-1-yl)ethoxy]-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;[4-[4-[8-(2-methoxyethoxy)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;[4-[4-[8-(3-methoxypropoxy)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;1-{4-[4-(8-hydroxyquinolin-7-yl)-phenoxy]-piperidin-l-yl}-propan-1-one;cyclopropyl-{4-[4-(8-hydroxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(8-hydroxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-[4-(2-chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(2-chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one;[4-(2-chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-cyclopropylmethanone;1-[4-(2-chloro-4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(2-chloro-4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one;1-[4-(2-methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(2-methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methylpropan-1-one;cyclopropyl-[4-(2-methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;1-[4-(2-methoxy-4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(3-fluoro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(3-fluoro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one;cyclopropyl-[4-(3-fluoro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;1-[4-(3-chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(3-chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one;[4-(3-chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-cyclopropylmethanone;2-methyl-1-[4-(3-methyl-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(3-methyl-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;4-(3-methyl-4-quinolin-3-yl-phenoxy)-piperidine-1-carboxylic acid methylester;1-[4-(3-methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(3-methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one;cyclopropyl-[4-(3-methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;1-[4-(2-methyl-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;2-methyl-1-[4-(2-methyl-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(2-methyl-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;1-[4-(2,5-difluoro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(2,5-difluoro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one;cyclopropyl-[4-(2,5-difluoro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;3-oxo-3-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propionitrile;1-{4-[2-fluoro-4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[2-fluoro-4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[2-fluoro-4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(8-chloroquinolin-7-yl)-2-fluoro-phenoxy]-piperidin-1-yl}-cyclopropylmethanone;{4-[4-(8-chloroquinolin-7-yl)-2-fluorophenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(8-chloroquinolin-7-yl)-2-fluorophenoxy]-piperidin-1-yl}-propan-1-one;1-{4-[2-fluoro-4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[2-fluoro-4-(8-methylquinolin-7-yl)-phenoxy]piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;cyclopropyl-{4-[2-fluoro-4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl})-methanone;1-{4-[2-fluoro-4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[2-fluoro-4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[2-fluoro-4-(4-methyl-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(4-aminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;1-{4-[4-(4-dimethylamino-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(4-dimethylaminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(4-amino-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(4-methylamino-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(4-methylaminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(4-morpholin-4-yl-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(4-morpholin-4-yl-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-(4-{4-[4-(4-methylpiperazin-1-yl)-quinolin-3-yl]-phenoxy}-piperidin-1-yl)-propan-1-one;(4-{4-[4-(4-methylpiperazin-1-yl)-quinolin-3-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone;3-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]oxazolidin-2-one;1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-butane-1,3-dione;1-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-pyrrolidin-2-one;4′-[1-((R)-tetrahydrofuran-2-carbonyl)-piperidin-4-yloxy]-biphenyl-4-carbonitrile;1-[4-(4-benzofuran-2-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-{4-[4-(1H-indol-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;1-[4-(4-benzo[b]thiophen-5-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-{4-[4-(1H-indazol-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;1-{4-[4-(1-methyl-1H-indazol-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;1-[4-(4-thieno[2,3-b]pyridin-5-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-{4-[4-(2-methyl-2H-indazol-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;1-[4-(4-[1,8]naphthyridin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-{4-[4-(2-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;(R)-tetrahydrofuran-2-yl-[4-(4-thieno[2,3-b]pyridin-5-yl-phenoxy)-piperidin-1-yl]-methanone;cyclopropyl-[4-(4-thieno[2,3-b]pyridin-5-yl-phenoxy)-piperidin-1-yl]-methanone;1-[4-(4-imidazo[1,2-a]pyridin-6-yl-phenoxy)-piperidin-1-yl]-propan-1-one;{4-[4-(4-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone;{4-[4-(4-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-cyclopropylmethanone;1-{4-[4-(4-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(8-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(8-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;(R)-tetrahydrofuran-2-yl-[4-(4-thieno[3,2-b]pyridin-6-yl-phenoxy)-piperidin-1-yl]-methanone;1-[4-(4-thieno[3,2-b]pyridin-6-yl-phenoxy)-piperidin-1-yl]-propan-1-one;{4-[4-(3-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(3-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;[4-(4-benzothiazol-5-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydrofuran-2-yl-methanone;[4-(4-benzothiazol-5-yl-phenoxy)-piperidin-1-yl]-cyclopropylmethanone;1-[4-(4-benzothiazol-5-yl-phenoxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-{4-[4-(1-methyl-1H-indazol-6-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(1-methyl-1H-indazol-6-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(6-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(6-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;7-[4-(1-propionyl-piperidin-4-yloxy)-phenyl]-quinoline-3-carbonitrile;7-{4-[1-((R)-tetrahydrofuran-2-carbonyl)-piperidin-4-yloxy]-phenyl}-quinoline-3-carbonitrile;7-[4-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-phenyl]-quinoline-3-carbonitrile;1-{4-[4-(3-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(3-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone;cyclopropyl-{4-[4-(3-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(8-methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(8-methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(5-methyl-imidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclopropyl-{4-[4-(8-methyl-imidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran2-yl-methanone;1-{4-[4-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(7-methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(7-methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-cyclopropyl-methanone;[4-(4-imidazo[1,5-a]pyridin-6-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydrofuran-2-yl-methanone;1-[4-(4-imidazo[1,5-a]pyridin-6-yl-phenoxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(4-imidazo[1,5-a]pyridin-6-yl-phenoxy)-piperidin-1-yl]-methanone;1-[4-(4-imidazo[1,5-a]pyridin-6-yl-phenoxy)-piperidine-1-carbonyl]-cyclopropanecarboxylicacid amide;(1-hydroxycyclopropyl)-[4-(4-imidazo[1,5-a]pyridin-6-yl-phenoxy)-piperidin-1-yl]-methanone;(1-hydroxycyclopropyl)-{4-[4-(8-methoxy-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;(1-hydroxymethylcyclopropyl)-{4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;(1-amino-cyclopropyl)-{4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;(1-hydroxycyclopropyl)-[4-(4-[1,2,4]triazolo[4,3-a]pyridin-7-yl-phenoxy)-piperidin-1-yl]-methanone;(R)-tetrahydrofuran-2-yl-[4-(4-[1,2,4]triazolo[4,3-a]pyridin-7-yl-phenoxy)-piperidin-1-yl]-methanone;cyclopropyl-[4-(4-[1,2,4]triazolo[4,3-a]pyridin-7-ylphenoxy)-piperidin-1-yl]-methanone;(1-hydroxycyclopropyl)-{4-[4-(5-methyl-imidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;2-hydroxy-2-methyl-1-{4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;(1-hydroxycyclopropyl)-{4-[4-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-(1-trifluoromethyl-cyclopropyl)-methanone;(1-aminocyclopropyl)-{4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(1-methyl-1H-indazol-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;[4-(4-imidazo[1,2-a]pyridin-6-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydro-furan-2-yl-methanone;1-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidine-1-carbonyl}-cyclopropanecarbonitrile;(1-methylcyclopropyl)-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;((S)-2,2-dimethylcyclopropyl)-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;(2,2-dimethylcyclopropyl)-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;[4-[4-[8-(4-methylpiperazin-1-yl)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;[4-[4-(8-amino-7-quinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;{4-[4-(8-methylaminoquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(8-methylamino-quinolin-7-yl)phenoxy]-piperidin-1-yl}-propan-1-one;(4-{4-[8-(2-methoxy-ethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone;1-(4-{4-[8-(2-methoxyethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one;(4-{4-[8-(2-di-methylaminoethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone;7-[4-(1-propionylpiperidin-4-yloxy)-phenyl]-quinoline-8-carbonitrile;[4-[4-[8-(dimethylamino)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;1-{4-[4-(8-dimethylaminoquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-dimethylaminoquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;(4-{4-[8-(2-pyrrolidin-1-yl-ethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone;1-(4-{4-[8-(2-pyrrolidin-1-yl-ethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one;7-[4-[[1-[(2R)-tetrahydrofuran-2-carbonyl]-4piperidyl]oxy]phenyl]quinoline-8-carboxamide;7-[4-(1-propionylpiperidin-4-yloxy)-phenyl]-quinoline-8-carboxylic acidamide; 1-(3-(4-(quinolin-3-yl)phenoxy)azetidin-1-yl)propan-1-one;2-methyl-1-(3-(4-(quinolin-3-yl)phenoxy)azetidin-1-yl)-propan-1-one;cyclopropyl(3-(4-(quinolin-3-yl)phenoxy)azetidin-1-yl)methanone;3-methyl-1-(3-(4-(quinolin-3-yl)phenoxy)azetidin-1-yl)butan-1-one;(S)-1-(3-(4-(quinolin-7-yl)phenoxy)pyrrolidin-1-yl)propan-1-one;(S)-1-(3-(4-(quinolin-3-yl)phenoxy)pyrrolidin-1-yl)propan-1-one;(R)-1-(3-(4-(quinolin-7-yl)phenoxy)pyrrolidin-1-yl)propan-1-one;(R)-1-(3-(4-(quinolin-3-yl)phenoxy)-pyrrolidin-1-yl)propan-1-one;1-(4-(4-(5-methylquinolin-7-yl)phenoxy)piperidin-1-yl)propan-1-one;cyclopropyl(4-(4-(5-methylquinolin-7-yl)phenoxy)piperidin-1-yl)methanone;1-(4-(4-(7-methylquinolin-5-yl)phenoxy)piperidin-1-yl)propan-1-one;cyclopropyl-{4-[4-(7-methylquinolin-5-yl)-phenoxy]-piperidin-1-yl}-methanone;1-(4-(4-(6-methylquinolin-5-yl)phenoxy)piperidin-1-yl)-propan-1-one;cyclopropyl(4-(4-(6-methylquinolin-5-yl)phenoxy)piperidin-1-yl)methanone;(R)-(4-(4-(5-methylquinolin-7-yl)phenoxy)piperidin-1-yl)(tetrahydrofuran-2-yl)methanone;(R)-(4-(4-(7-methylquinolin-5-yl)phenoxy)piperidin-1-yl)(tetrahydrofuran-2-yl)methanone;(R)-(4-(4-(6-methylquinolin-5-yl)phenoxy)piperidin-1-yl)(tetrahydrofuran-2-yl)methanone;(±)-(7S,8aS)-7-(4-(8-methylquinolin-7-yl)phenoxy)hexahydroindolizin-3(2H)-one;(±)-(7R,8aS)-7-(4-(8-methylquinolin-7-yl)phenoxy)hexahydroindolizin-3(2H)-one;2,2,2-trifluoro-1-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-ethanone;2,2-difluoro-1-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;2-fluoro-1-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{exo-3-[4-(8-methylquinolin-7-yl)-phenoxy]-8-aza-bicyclo[3.2.1]oct-8-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{exo-3-[4-(8-methylquinolin-7-yl)-phenoxy]-8-aza-bicyclo[3.2.1]oct-8-yl}-propan-1-one;{2-methyl-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{2-methyl-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;1-{2-methyl-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{2-methyl-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{cis-3-fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{cis-3-fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{cis-3-fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{endo-3-[4-(8-methylquinolin-7-yl)-phenoxy]-8-aza-bicyclo[3.2.1]oct-8-yl}-propan-1-one;cyclopropyl-{endo-3-[4-(8-methylquinolin-7-yl)-phenoxy]-8-aza-bicyclo[3.2.1]oct-8-yl}-methanone;{endo-3-[4-(8-methylquinolin-7-yl)-phenoxy]-8-aza-bicyclo[3.2.1]oct-8-yl}-(R)-tetrahydrofuran-2-yl-methanone;{(trans)-3-fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{trans-3-fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{trans-3-fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{3-methyl-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{3-methyl-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{3-methyl-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(6-phenylpyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;2-methyl-1-{4-[4-(6-phenylpyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(6-phenylpyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(6-phenylpyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(5-phenylpyridin-3-yl)-phenoxy]piperidin-1-yl}-propan-1-one;2-methyl-1-{4-[4-(5-phenylpyridin-3-yl)-phenoxy]piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(5-phenylpyridin-3-yl)-phenoxy]piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(5-phenylpyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(6-morpholin-4-yl-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(6-morpholin-4-yl-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(6-morpholin-4-yl-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(6-phenoxypyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(6-phenoxy-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(6-phenoxypyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(6-phenylaminopyridin-3-yl)phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(6-phenylaminopyridin-3-yl)phenoxy]-piperidin-1-yl})-methanone;cyclobutyl-{4-[4-(6-phenylamino-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-[4-(2′-fluoro-3′-pyridin-2-yl-biphenyl-4-yloxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(2′-fluoro-3′-pyridin-2-yl-biphenyl-4-yloxy)-piperidin-1-yl]-methanone;1-{4-[4-(5-phenoxypyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclobutyl-[4-(2′-fluoro-3′-pyridin-2-yl-biphenyl-4-yloxy)-piperidin-1-yl]-methanone;cyclopropyl-{4-[4-(5-phenoxypyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(5-phenoxypyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(5-phenylamino-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;1-{4-[4-(2-phenyl-pyridin-4-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(2-phenylpyridin-4-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(2-phenylaminopyridin-4-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(2-phenylaminopyridin-4-yl)-phenoxy]-piperidin-1-yl}-methanone;1-[4-(2′-methyl-3′-pyridin-2-yl-biphenyl-4-yloxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(2′-methyl-3′-pyridin-2-yl-biphenyl-4-yloxy)-piperidin-1-yl]-methanone;cyclobutyl-[4-(2′-methyl-3′-pyridin-2-yl-biphenyl-4-yloxy)-piperidin-1-yl]-methanone;1-{4-[4-(2-phenoxypyridin-4-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;1-{4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(4-methoxypyrazolo[1,5-a]-pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(3-chloroisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(3-chloroisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-cyclopropylmethanone;1-{4-[4-(3-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(3-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(3-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(3-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(1-chloroisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(1-chloroisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-cyclopropylmethanone;1-{4-[4-(3-dimethylaminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;1-{4-[4-(3-amino-isoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(3-aminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl})-cyclopropylmethanone;{4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl})-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(1-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl})-propan-1-one;1-{4-[4-(4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclobutyl-{4-[4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(1-chloroisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-cyclobutylmethanone;{4-[4-(1-chloro-isoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(3-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(1-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(1-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(1-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclobutyl-{4-[4-(1-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclopropyl-{4-[4-(1-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(3-aminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(3-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(1-ethyl-isoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(1-cyclopropylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl})-propan-1-one;{4-[4-(1-cyclopropylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(7-methoxy-6-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(7-methoxy-6-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(7-methoxy-6-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(6-fluoro-7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(6-fluoro-7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(6-fluoro-7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(6-chloro-7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(6-chloro-7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-cyclopropylmethanone;{4-[4-(6-chloro-7-methoxyquinolin-3-yl)-phenoxy]piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(6-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(3-isopropoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(1-morpholin-4-yl-isoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(1-dimethylaminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahyrofuran-2-ylmethananone;{4-[4-(1-amino-isoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(1-dimethylaminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(1-methylaminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(4-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl})-propan-1-one;cyclopropyl-{4-[4-(4-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(4-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(5-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(5-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(5-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(5-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(5-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(5-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;cyclopropyl-[4-(4-isoquinolin-6-yl-phenoxy)-piperidin-1-yl]-methanone;[4-[4-(6-isoquinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;{4-[4-(5-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-[4-[4-(1,4-dimethyl-6-isoquinolyl)phenoxy]-1-piperidyl]propan-1-one;cyclopropyl-[4-[4-(1,4-dimethyl-6-isoquinolyl)phenoxy]-1-piperidyl]methanone;[4-[4-(1,4-dimethyl-6-isoquinolyl)-phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;1-[4-[4-(1,5-dimethyl-6-isoquinolyl)phenoxy]-1-piperidyl]propan-1-one;cyclopropyl-[4-[4-(1,5-dimethyl-6-isoquinolyl)-phenoxy]-1-piperidyl]methanone;[4-[4-(1,5-dimethyl-6-isoquinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;[4-[4-(8-cyclopropyl-7-quinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;{4-[4-(3-ethylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;cyclopropyl-{4-[4-(7-fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(7-fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(7-fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(3-cyclopropylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;cyclopropyl-{4-[4-(1-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(7-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(6-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(6-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(6-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(8-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(8-methyl-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;4-(3′,4′-dimethoxybiphenyl-4-yloxy)-piperidine-1-carboxylic acidtert-butyl ester; 4-(4′-cyanobiphenyl-4-yl-oxy)-piperidine-1-carboxylicacid tert-butyl ester;1-[4-(3′,4′-dimethoxy-biphenyl-4-yloxy)-piperidin-1-yl]-propan-1-one;1-[4-(3′,4′-dimethoxybiphenyl-4-yloxy)-piperidin-1-yl]-2-methyl-propan-1-one;4′-(1-propionylpiperidin-4-yloxy)-biphenyl-4-carbonitrile;4′-(1-isobutyrylpiperidin-4-yloxy)-biphenyl-4-carbonitrile;4′-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-biphenyl-4-carbonitrile;1-[4-(3-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(3-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;1-{4-[4-(5,6-dimethoxypyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(5,6-dimethoxypyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-[4-(3′,4′-dichlorobiphenyl-4-yloxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(3′,4′-dichlorobiphenyl-4-yloxy)-piperidin-1-yl]-methanone;1-{4-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;1-[4-(4′-benzyloxy-2′-fluorobiphenyl-4-yloxy)-piperidin-1-yl]-propan-1-one;[4-(4′-benzyloxy-2′-fluorobiphenyl-4-yloxy)-piperidin-1-yl]-cyclopropylmethanone;1-[4-(5′-benzyloxy-3′-fluorobiphenyl-4-yloxy)-piperidin-1-yl]-propan-1-one;[4-(5′-benzyloxy-3′-fluorobiphenyl-4-yloxy)-piperidin-1-yl]-cyclopropylmethanone;1-[4-(4′-phenoxybiphenyl-4-yloxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(4′-phenoxybiphenyl-4-yloxy)-piperidin-1-yl]-methanone;1-[4-(3′-phenoxybiphenyl-4-yloxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(3′-phenoxy-biphenyl-4-yloxy)-piperidin-1-yl]-methanone;2-methyl-1-(4-((4-(quinolin-7-yl)phenyl)sulfonyl)piperidin-1-yl)propan-1-one;1-[4-(4-isoquinolin-7-yl-benzene-sulfonyl)-piperidin-1-yl]-2-methylpropan-1-one;1-[4-(4-isoquinolin-6-yl-benzenesulfonyl)-piperidin-1-yl]-2-methyl-propan-1-one;1-[4-(4-benzofuran-5-yl-benzenesulfonyl)-piperidin-1-yl]-2-methyl-propan-1-one;1-(4-((4-(quinolin-7-yl)phenyl)thio)piperidin-1-yl)propan-1-one;1-(4-((4-(isoquinolin-6-yl)phenyl)thio)piperidin-1-yl)propan-1-one;1-(4-((4-(quinolin-3-yl)phenyl)thio)piperidin-1-yl)propan-1-one;1-(4-((4-(isoquinolin-4-yl)phenyl)thio)piperidin-1-yl)propan-1-one;1-(4-((4-(isoquinolin-6-yl)phenyl)thio)piperidin-1-yl)propan-1-one;1-(4-((4-(isoquinolin-6-yl)phenyl)thio)piperidin-1-yl)-2-methylpropan-1-one;2-methyl-1-(4-((4-(quinolin-3-yl)phenyl)thio)piperidin-1-yl)propan-1-one;1-(4-((4-(isoquinolin-4-yl)phenyl)thio)piperidin-1-yl)-2-methylpropan-1-one;1-{4-[methyl-(4-quinolin-3-yl-phenyl)-amino]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[methyl-(4-quinolin-3-yl-phenyl)-amino]-piperidin-1-yl}-methanone;1-[4-(4-quinolin-3-yl-phenylamino)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(4-quinolin-3-yl-phenylamino)-piperidin-1-yl]-methanone;{4-[methyl-(4-quinolin-3-yl-phenyl)-amino]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanoneand salts of such compounds, e.g., pharmaceutically acceptable salts.

Additional compounds according to Formula I may include, for example:N-ethyl-4-[4-(2-hydroxy-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-pyrrolidin-1-ylethyl)piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-morpholinoethyl)piperidine-1-carboxamide;(4-isopropylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;(4-methylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(4-morpholino-1-piperidyl)methanone;(4-ethyllpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;N-ethyl-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)-phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-ethoxyoxy-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-methoxyoxy-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-(cyclopropylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]-piperidine-1-carboxamide;N-isobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-(2-methoxyethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-Isopropoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isobutoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-(2-dimethylaminoethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;2-morpholinoethyl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate;2-pyrrolidin-1-ylethyl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate;N-[2-(1H-imidazol-4-yl)ethyl]-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-tetrahydropyran-4-yl-piperidine-1-carboxamide;isobutyl 4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate;allyl 4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate;N-cyclobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;cyclopropylmethyl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate;4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbohydroxamic acid;2-methoxyethyl4-[4-(8-methyl-7-quinolyl)-phenoxy]piperidine-1-carboxylate;tetrahydropyran-4-yl4-[4-(8-methyl-7-quinolyl)phenoxy]-piperidine-1-carboxylate;tetrahydropyran-3-yl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(oxazinan-2-yl)methanone;tetrahydrofuran-3-yl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate;N-(cyclobutylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;cyclobutyl 4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate;azepan-1-yl-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;N-butyl-4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-ethyl-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-isobutyl-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-propyl-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-(2-methoxyethyl)-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-(cyclopropyl-methyl)-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-isopropoxy-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-isopropyl-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-isobutoxy-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-isopentyl-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-ethoxy-piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carbohydroxamicacid;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-propoxy-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-ethyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;N-isobutyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-(cyclopropylmethyl)-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]-N-propoxypiperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carbohydroxamic acid;N-ethoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-ethoxy-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide;N-isobutyl-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;N-ethyl-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-isobutyl-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-propyl-piperidine-1-carboxamide;N-(cyclopropylmethyl)-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]piperidine-1-carboxamide;4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-(3-pyridyl)-piperidine-1-carboxamide;N-(2-methoxyethyl)-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;[4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-1-piperidyl]-(4-methylpiperazin-1-yl)methanone;N,N-dimethyl-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-isobutoxy-4-[4-(5-methyl-imidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;isobutyl4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxylate;N-isopropyl-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-(1-methylpyrazol-4-yl)piperidine-1-carboxamide;tert-butyl4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxylate;4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-(2,2,2-trifluoro-ethyl)piperidine-1-carboxamide;4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-propoxy-piperidine-1-carboxamide;N-ethoxy-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamidel2-amino-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]ethanone 2HCl;(2R)-2-amino-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]propan-1-one2HCl;N-methoxy-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;(2S)-2-amino-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]propan-1-one2HCl;4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carbohydroxamicacid;2-(dimethylamino)-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]ethanone;4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;[(2R)-1-methylpyrrolidin-2-yl]-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;[(2S)-1-methylpyrrolidin-2-yl]-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;S-isopropyl 4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbothioate;2-amino-2-methyl-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-propan-1-one;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-[(2R)-pyrrolidin-2-yl]methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-[(2S)-pyrrolidin-2-yl]methanone;[1-(methylamino)cyclopropyl]-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;3-amino-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]propan-1-one;2-isopropoxy-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]ethanone;[2-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-2-oxo-ethyl]acetate;2-hydroxy-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]ethanone;(1-aminocyclobutyl)-[4-[4-(8-methyl-7-quinolyl)-phenoxy]-1-piperidyl]-methanone;N-ethyl-4-(4-imidazo[1,2-a]pyridin-7-ylphenoxy)piperidine-1-carboxamide;N-ethyl-4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]-N-propyl-piperidine-1-carboxamide;N-isobutyl-4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]piperidine-1-carboxamide;N-isobutyl-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carbohydroxamicacid;N,N-dimethyl-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;[4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]-1-piperidyl]-pyrrolidin-1-yl-methanone;[(3S)-3-fluoropyrrolidin-1-yl]-[4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]-1-piperidyl]methanone;[(3R)-3-fluoropyrrolidin-1-yl]-[4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]-1-piperidyl]-methanone;4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]-N-methylsulfanyl-piperidine-1-carboxamide;N-ethylsulfanyl-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-methylsulfanyl-piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-ethylsulfanyl-piperidine-1-carboxamide;1-[4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carbonyl]pyrrolidin-2-one;1-[4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carbonyl]pyrrolidin-2-one;4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]-N-propyl-piperidine-1-carboxamide;N-ethyl-4-[4-(2-fluoro-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamideand salts of such compounds, e.g., pharmaceutically acceptable salts.

Compounds according to Formula III may include. for example:1-[4-(4-isoquinolin-6-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;2-methyl-1-[4-(4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(2-fluoro-4-quinolin-3-yl-phenoxy)piperidin-1-yl]propan-1-one;1-[4-(2-fluoro-4-quinolin-3-ylphenoxy)-piperidin-1-yl]-2-methylpropan-1-one;1-[4-(4-1,5-naphthyridin-3-yl-phenoxy)piperidin-1-yl]-propan-1-one;2-methyl-1-[4-(4-1,5-naphthyridin-3-yl-phenoxy)piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(4-1,5-naphthyridin-3-yl-phenoxy)piperidin-1-yl]-methanone;1-{4-[4-(2-chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(2-chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-cyclopropylmethanone;1-{4-[4-(2-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;1-{4-[4-(8-fluoro-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-fluoro-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(8-fluoroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(8-fluoro-2-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-fluoro-2-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(8-fluoro-2-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(5-fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(5-fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(5-fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(5-fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclopropyl-{4-[4-(7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;1-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclopropyl-[4-(4-quinolin-2-yl-phenoxy)-piperidin-1-yl]-methanone;1-[4-(4-quinolin-2-yl-phenoxy)-piperidin-1-yl]-propan-1-one;cyclobutyl-[4-(4-quinolin-2-yl-phenoxy)-piperidin-1-yl]-methanone;[4-(4-quinolin-2-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydrofuran-2-yl-methanone;1-[4-(4-isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(4-isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;cyclobutyl-[4-(4-isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;[4-(4-isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(4-chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(4-chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-cyclopropylmethanone;{4-[4-(4-chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-cyclobutylmethanone;1-{4-[4-(4-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;1-{4-[4-(6-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(6-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(6,7-dimethoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(6,7-dimethoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(8-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(8-chloroquinolin-7-yl)-phenoxy]piperidin-1-yl}-cyclopropylmethanone;1-{4-[4-(4-methylquinolin-3-yl)-phenoxy]piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(4-methylquinolin-3-yl)-phenoxy]piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(4-methylquinolin-3-yl)-phenoxy]piperidin-1-yl}-methanone;1-{4-[4-(7-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(7-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-[4-(4-quinoxalin-2-yl-phenoxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(4-quinoxalin-2-yl-phenoxy)-piperidin-1-yl]-methanone;[4-(4-quinoxalin-2-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(S)-tetrahydrofuran-2-yl-methanone;{4-[4-(4-chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl})-propane-1,2-dione;isoxazolidin-2-yl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;[4-(4-isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-isoxazolidin-2-yl-methanone;isoxazolidin-2-yl-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(4-chloroquinolin-3-yl)-phenoxy]piperidin-1-yl}-isoxazolidin-2-yl-methanone;{4-[4-(8-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-isoxazolidin-2-yl-methanone;isoxazolidin-2-yl-{4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-{4-[4-(7-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-[4-(4-quinoxalin-2-yl-phenoxy)-piperidin-1-yl]-methanone;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidmethoxyamide;4-[4-(4-methyl-quinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidmethoxy-methyl-amide;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidethylamide;4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidmethylamide;4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidethylamide;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidhydroxyamide;N-ethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N,N-dimethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;ethyl 4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate;N-methoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropyl-4-[4-(8-methyl-7-quinolyl)-phenoxy]piperidine-1-carboxamide;N-ethoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-pyrrolidin-1-yl-methanone;N-methyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)-phenoxy]-N-propyl-piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(1-piperidyl)methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-morpholinomethanone;cyclopropyl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;cyclobutyl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;cyclopentyl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydrofuran-2-yl-methanone;[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-(S)-tetrahydrofuran-2-yl-methanone;2-methoxy-1-[4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-ethanone;[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-(tetrahydropyran-2-yl)-methanone;[4-(4-quinolin-3-yl-phenoxyl)-piperidin-1-yl]-(tetrahydrofuran-3-yl)-methanone;(R)-2-methoxy-1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;(S)-2-methoxy-1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;2-hydroxy-1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-ethanone;[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-(tetrahydropyran-2-yl)-methanone;1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-ethanone;2-methyl-1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;2,2-dimethyl-1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;(2-methyltetrahydrofuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;(2-methyl-1,3-dioxolan-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;2-methanesulfonyl-1-[4-(4-quinolin-3-yl-phenoxy)piperidin-1-yl]-ethanone;(1,1-dioxidotetrahydrothiophen-2-yl)(4-(4-(quinolin-3-yl)phenoxy)piperidin-1-yl)methanone;(3,3-difluorocyclobutyl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;(R)-5-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-dihydrofuran-2-one;(3-methylfuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;(3,5-dimethylfuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;oxazol-2-yl-[4-(4-quinolin-3-yl-phenoxy)piperidin-1-yl]-methanone;isoxazol-3-yl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;isothiazol-3-yl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-(tetrahydrofuran-2-yl)-methanone;phenyl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;(2,5-dimethylphenyl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;[3-(1H-imidazol-2-yl)-phenyl]-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;[3-(1H-benzimidazol-2-yl)-phenyl]-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;N-methoxy-4-[4-(8-methoxy-7-quinolyl)phenoxy]piperidine-1-carboxamide;1-propionylpiperidine-4-carboxylic acidmethyl-(4-quinolin-7-yl-phenyl)-amide;1-propionylpiperidine-4-carboxylic acid(4-isoquinolin-6-yl-phenyl)-methylamide;oxo-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-acetaldehyde;((2R,3S)/(2S,3R)-3-methyltetrahydrofuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)piperidin-1-yl]-methanone;((2R,3S,5R)/(2S,3R,5S)-3,5-dimethyltetrahydrofuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;((2R,3S,5R)/(2S,3R,5S)-3,5-dimethyl-tetrahydrofuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;3-[4-(1-methanesulfonyl-piperidin-4-yloxy)-phenyl]-quinoline;(4,4-difluorotetrahydrofuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;(4,4-difluorotetrahydrofuran-2-yl)-{4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;(4,4-difluorotetrahydrofuran-2-yl)-{4-[4-(1-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;5-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-dihydrofuran-3-one;1-{4-[4-(8-ethoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-ethoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(8-isopropoxy-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-isopropoxy-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;1-(4-{4-[8-(2-morpholin-4-yl-ethoxy)quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one;cyclopropyl-(4-{4-[8-(2-morpholin-4-yl-ethoxy)-quinolin-7-yl]-phenoxyl}-piperidin-1-yl)-methanone;1-(4-{4-[8-(2-pyrrolidin-1-yl-ethoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one;cyclopropyl-(4-{4-[8-(2-pyrrolidin-1-yl-ethoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-methanone;1-(4-{4-[8-(3-pyrrolidin-1-yl-propoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)propan-1-one;cyclopropyl-(4-{4-[8-(3-pyrrolidin-1-yl-propoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-methanone;1-[4-[4-[8-[2-(4-methylpiperazin-1-yl)ethoxy]-7-quinolyl]phenoxy]-1-piperidyl]propan-1-one;1-[4-[4-[8-(2-methoxyethoxy)-7-quinolyl]phenoxy]-1-piperidyl]propan-1-one;1-[4-[4-[8-(3-methoxypropoxy)-7-quinolyl]phenoxy]-1-piperidyl]propan-1-one;{4-[4-(8-isopropoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(8-ethoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;(4-{4-[8-(2-morpholin-4-yl-ethoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone;(4-{4-[8-(2-pyrrolidin-1-yl-ethoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-ylmethanone;(4-{4-[8-(3-pyrrolidin-1-yl-propoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-ylmethanone;[4-[4-[8-[2-(4-methylpiperazin-1-yl)ethoxy]-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;[4-[4-[8-(2-methoxyethoxy)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;[4-[4-[8-(3-methoxypropoxy)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;1-{4-[4-(8-hydroxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-hydroxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(8-hydroxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-[4-(2-chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(2-chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one;[4-(2-chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-cyclopropyl-methanone;1-[4-(2-chloro-4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(2-chloro-4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-2-methylpropan-1-one;1-[4-(2-methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(2-methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one;cyclopropyl-[4-(2-methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;1-[4-(2-methoxy-4-quinolin-7-yl-phenoxy)piperidin-1-yl]-propan-1-one;1-[4-(3-fluoro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(3-fluoro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methylpropan-1-one;cyclopropyl-[4-(3-fluoro-4-quinolin-3-ylphenoxy)-piperidin-1-yl]-methanone;1-[4-(3-chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(3-chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methylpropan-1-one;[4-(3-chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-cyclopropylmethanone;2-methyl-1-[4-(3-methyl-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(3-methyl-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;4-(3-methyl-4-quinolin-3-yl-phenoxy)-piperidine-1-carboxylic acid,methyl ester;1-[4-(3-methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(3-methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one;cyclopropyl-[4-(3-methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;1-[4-(2-methyl-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;2-methyl-1-[4-(2-methyl-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(2-methyl-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;3-oxo-3-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propionitrile;1-{4-[2-fluoro-4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[2-fluoro-4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[2-fluoro-4-(8-methoxy-quinolin-7-yl)-phenoxy]piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(8-chloroquinolin-7-yl)-2-fluoro-phenoxy]-piperidin-1-yl}-cyclopropylmethanone;{4-[4-(8-chloroquinolin-7-yl)-2-fluoro-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(8-chloroquinolin-7-yl)-2-fluorophenoxy]-piperidin-1-yl}-propan-1-one;1-{4-[2-fluoro-4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[2-fluoro-4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;cyclopropyl-{4-[2-fluoro-4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[2-fluoro-4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[2-fluoro-4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[2-fluoro-4-(4-methyl-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(4-aminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;1-(4-(4-(4-(dimethylamino)quinolin-3-yl)phenoxy)piperidin-1-yl)propan-1-one;{4-[4-(4-dimethylaminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(4-amino-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(4-methylaminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(4-methylaminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(4-morpholin-4-yl-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(4-morpholin-4-yl-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-(4-{4-[4-(4-methylpiperazin-1-yl)-quinolin-3-yl]-phenoxy}-piperidin-1-yl)-propan-1-one;(4-{4-[4-(4-methylpiperazin-1-yl)-quinolin-3-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone;3-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-oxazolidin-2-one;1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-butane-1,3-dione;1-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-pyrrolidin-2-one;1-[4-(4-[1,8]naphthyridin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-{4-[4-(2-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(4-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(4-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl})-cyclopropylmethanone;1-{4-[4-(4-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(8-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(8-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(3-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(3-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl})-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(6-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(6-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;7-[4-(1-propionyl-piperidin-4-yloxy)-phenyl]-quinoline-3-carbonitrile;7-{4-[1-((R)-tetrahydrofuran-2-carbonyl)-piperidin-4-yloxy]-phenyl}-quinoline-3-carbonitrile;7-[4-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-phenyl]-quinoline-3-carbonitrile;1-{4-[4-(3-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(3-methyl-quinolin-7-yl)-phenoxy]-piperidin-l-yl}-(R)-tetrahydrofuran-2-yl-methanone;cyclopropyl-{4-[4-(3-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;(1-hydroxycyclopropyl)-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(1-trifluoromethylcyclopropyl)-methanone;(1-aminocyclopropyl)-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidine-1-carbonyl})cyclopropanecarbonitrile;(1-methylcyclopropyl)-{4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;((S)-2,2-dimethylcyclopropyl)-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;(2,2-dimethylcyclopropyl)-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;[4-[4-[8-(4-methylpiperazin-1-yl)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;[4-[4-(8-amino-7-quinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;{4-[4-(8-methylaminoquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(8-methylaminoquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;(4-{4-[8-(2-methoxyethyl-amino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone;1-(4-{4-[8-(2-methoxy-ethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one;(4-{4-[8-(2-dimethylamino-ethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone;7-[4-(1-propionyl-piperidin-4-yloxy)-phenyl]-quinoline-8-carbonitrile;[4-[4-[8-(dimethylamino)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;1-{4-[4-(8-dimethylamino-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-dimethylaminoquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;(4-{4-[8-(2-pyrrolidin-1-yl-ethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone;1-(4-{4-[8-(2-pyrrolidin-1-yl-ethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one;7-[4-[[1-[(2R)-tetrahydrofuran-2-carbonyl]-4piperidyl]oxy]phenyl]quinoline-8-carboxamide;7-[4-(1-propionyl-piperidin-4-yloxy)-phenyl]-quinoline-8-carboxylic acidamide; cyclopropyl(3-(4-(quinolin-3-yl)phenoxy)azetidin-1-yl)methanone;1-(4-(4-(5-methylquinolin-7-yl)phenoxy)-piperidin-1-yl)propan-1-one;cyclopropyl(4-(4-(5-methylquinolin-7-yl)phenoxy)piperidin-1-yl)methanone;(R)-(4-(4-(5-methylquinolin-7-yl)phenoxy)piperidin-1-yl)(tetrahydrofuran-2-yl)methanone;2,2,2-trifluoro-1-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-ethanone;2,2-difluoro-1-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;2-fluoro-1-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;1-{4-[4-(3-chloroisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(3-chloroisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-cyclopropyl-methanone;1-{4-[4-(3-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(3-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl})-methanone;cyclobutyl-{4-[4-(3-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(3-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(1-chloroisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(1-chloroisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-cyclopropylmethanone;1-{4-[4-(3-dimethylaminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;1-{4-[4-(3-aminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(3-aminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-cyclopropyl-methanone;1-{4-[4-(1-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(1-chloroisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-cyclobutyl-methanone;{4-[4-(1-chloroisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone;1-{4-[4-(3-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(1-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone;{4-[4-(1-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(1-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclobutyl-{4-[4-(1-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclopropyl-{4-[4-(1-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(3-aminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(3-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(1-ethylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(1-cyclopropylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(1-cyclopropyl-isoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(7-methoxy-6-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(7-methoxy-6-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(7-methoxy-6-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(6-fluoro-7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(6-fluoro-7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(6-fluoro-7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(6-chloro-7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(6-chloro-7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-cyclopropylmethanone;{4-[4-(6-chloro-7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(6-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(3-isopropoxy-isoquinolin-6-yl)-phenoxy]-piperidin-1-yl})-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(1-morpholin-4-yl-isoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(1-dimethylaminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-ylmethananone;{4-[4-(1-aminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(1-dimethylaminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(1-methylaminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(4-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(4-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(4-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(5-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl})-propan-1-one;cyclopropyl-{4-[4-(5-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(5-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(5-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(5-methoxy-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(5-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;cyclopropyl-[4-(4-isoquinolin-6-yl-phenoxy)-piperidin-1-yl]-methanone;[4-[4-(6-isoquinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;{4-[4-(5-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-[4-[4-(1,4-dimethyl-6-isoquinolyl)phenoxy]-1-piperidyl]propan-1-one;cyclopropyl-[4-[4-(1,4-dimethyl-6-isoquinolyl)phenoxy]-1-piperidyl]methanone;[4-[4-(1,4-dimethyl-6-isoquin-olyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;1-[4-[4-(1,5-dimethyl-6-isoquinolyl)phenoxy]-1-piperidyl]propan-1-one;cyclopropyl-[4-[4-(1,5-dimethyl-6-isoquinolyl)-phenoxy]-1-piperidyl]methanone;[4-[4-(1,5-dimethyl-6-isoquinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;[4-[4-(8-cyclopropyl-7-quinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;{4-[4-(3-ethylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;cyclopropyl-{4-[4-(7-fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(7-fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(7-fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(3-cyclopropylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;cyclopropyl-{4-[4-(1-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(7-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(6-methyl-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(6-methyl-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(6-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(8-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(8-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-[4-(3-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one;cyclopropyl-[4-(3-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;1-(4-((4-(quinolin-7-yl)phenyl)thio)piperidin-1-yl)propan-1-one;1-(4-((4-(isoquinolin-6-yl)phenyl)thio)piperidin-1-yl)propan-1-one;1-(4-((4-(quinolin-3-yl)phenyl)thio)piperidin-1-yl)propan-1-one;1-(4-((4-(isoquinolin-6-yl)phenyl)thio)piperidin-1-yl)propan-1-one;1-(4-((4-(isoquinolin-6-yl)phenyl)thio)piperidin-1-yl)-2-methylpropan-1-one;and2-methyl-1-(4-((4-(quinolin-3-yl)phenyl)thio)piperidin-1-yl)propan-1-one;and salts thereof, e.g., pharmaceutically acceptable salts thereof.

Additional compounds according to Formula III may include, for example:N-ethyl-4-[4-(2-hydroxy-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-pyrrolidin-1-ylethyl)piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-morpholinoethyl)piperidine-1-carboxamide;(4-isopropylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;(4-methylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(4-morpholino-1-piperidyl)methanone;(4-ethylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;N-(cyclopropylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-(2-methoxyethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isobutoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-(2-dimethylaminoethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-[2-(1H-imidazol-4-yl)ethyl]-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-tetrahydropyran-4-yl-piperidine-1-carboxamide;N-cyclobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]-piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbohydroxamic acid;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(oxazinan-2-yl)methanone;N-(cyclobutylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;azepan-1-yl-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide;N-ethyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;N-isobutyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-iso-quinolyl)phenoxy]piperidine-1-carboxamide;N-(cyclopropylmethyl)-4-[4-(1-methyl-6-iso-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]-piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]-N-propoxypiperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carbohydroxamic acid;N-ethoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-ethoxy-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(4-methyl-3-quinolyl)-phenoxy]piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide;N-isobutyl-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;2-amino-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]ethanone;(2R)-2-amino-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]propan-1-one2HCl;(2S)-2-amino-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]propan-1-one2HCl;2-(dimethylamino)-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-ethanone;[(2R)-1-methylpyrrolidin-2-yl]-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;[(2S)-1-methylpyrrolidin-2-yl]-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;S-isopropyl 4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbothioate;2-amino-2-methyl-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-propan-1-one;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-[(2R)-pyrrolidin-2-yl]methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-[(2S)-pyrrolidin-2-yl]methanone;[1-(methylamino)cyclopropyl]-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;3-amino-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]propan-1-one;2-isopropoxy-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]ethanone;[2-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-2-oxo-ethyl]acetate;2-hydroxy-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]ethanone;(1-aminocyclobutyl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-methylsulfanyl-piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-ethylsulfanyl-piperidine-1-carboxamide;1-[4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carbonyl]pyrrolidin-2-one;N-ethyl-4-[4-(2-fluoro-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamideand salts thereof, e.g., pharmaceutically acceptable salts.

Compounds according to Formula IV may include, for example:2-methyl-1-[4-(4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-{4-[4-(8-fluoroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-fluoroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(8-fluoroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(8-fluoro-2-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-fluoro-2-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(8-fluoro-2-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;cyclobutyl-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(8-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-cyclopropylmethanone;{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(S)-tetrahydrofuran-2-yl-methanone;isoxazolidin-2-yl-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(8-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl})-isoxazolidin-2-yl-methanone;isoxazolidin-2-yl-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidmethylamide;4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidethylamide;N-ethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N,N-dimethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;ethyl 4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate;N-methoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-ethoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-pyrrolidin-1-yl-methanone;N-methyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(1-piperidyl)methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-morpholinomethanone;N-methoxy-4-[4-(8-methoxy-7-quinolyl)phenoxy]piperidine-1-carboxamide;(4,4-difluorotetrahydrofuran-2-yl)-{4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-l-yl}-methanone;1-{4-[4-(8-ethoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-ethoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(8-isopropoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-isopropoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;1-(4-{4-[8-(2-morpholin-4-yl-ethoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one;cyclopropyl-(4-{4-[8-(2-morpholin-4-yl-ethoxy)-quinolin-7-yl]-phenoxyl}-piperidin-1-yl)-methanone;1-(4-{4-[8-(2-pyrrolidin-1-yl-ethoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one;cyclopropyl-(4-{4-[8-(2-pyrrolidin-1-yl-ethoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-methanone;1-(4-{4-[8-(3-pyrrolidin-1-yl-propoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one;cyclopropyl-(4-{4-[8-(3-pyrrolidin-1-yl-propoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-methanone;1-[4-[4-[8-[2-(4-methylpiperazin-1-yl)ethoxy]-7-quinolyl]phenoxy]-1-piperidyl]propan-1-one;1-[4-[4-[8-(2-methoxyethoxy)-7-quinolyl]phenoxy]-1-piperidyl]propan-1-one;1-[4-[4-[8-(3-methoxypropoxy)-7-quinolyl]phenoxy]-1-piperidyl]propan-1-one;{4-[4-(8-isopropoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(8-ethoxy-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;(4-{4-[8-(2-morpholin-4-yl-ethoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone;(4-{4-[8-(2-pyrrolidin-1-yl-ethoxy)-quinolin-7-yl]-phenoxy})-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone;(4-{4-[8-(3-pyrrolidin-1-yl-propoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-ylmethanone;[4-[4-[8-[2-(4-methylpiperazin-1-yl)ethoxy]-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;[4-[4-[8-(2-methoxyethoxy)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;[4-[4-[8-(3-methoxypropoxy)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;1-{4-[4-(8-hydroxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-hydroxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(8-hydroxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-[4-(2-chloro-4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-[4-(2-chloro-4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-2-methylpropan-1-one;1-[4-(2-methoxy-4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-propan-1-one;1-{4-[2-fluoro-4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[2-fluoro-4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[2-fluoro-4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-l-yl}-(R)-tetrahydrofuran-2-yl-methanone;{4-[4-(8-chloroquinolin-7-yl)-2-fluorophenoxy]-piperidin-l-yl}-cyclopropyl-methanone;{4-[4-(8-chloroquinolin-7-yl)-2-fluoro-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(8-chloroquinolin-7-yl)-2-fluoro-phenoxy]piperidin-1-yl}-propan-1-one;1-{4-[2-fluoro-4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[2-fluoro-4-(8-methylquinolin-7-yl)-phenoxy]piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;cyclopropyl-{4-[2-fluoro-4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(2-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(4-chloroquinolin-7-yl)-phenoxy]piperidin-1-yl}-(R)-tetrahydrofuran-2-ylmethanone;{4-[4-(4-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}cyclopropylmethanone;1-{4-[4-(4-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(8-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(8-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(3-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(3-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl})-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(6-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(6-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;7-[4-(1-propionylpiperidin-4-yloxy)-phenyl]-quinoline-3-carbonitrile;7-{4-[1-((R)-tetrahydrofuran-2-carbonyl)-piperidin-4-yloxy]-phenyl}-quinoline-3-carbonitrile;7-[4-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-phenyl]-quinoline-3-carbonitrile;1-{4-[4-(3-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{4-[4-(3-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;cyclopropyl-{4-[4-(3-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;(1-hydroxycyclopropyl)-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(1-trifluoromethylcyclopropyl)-methanone;(1-aminocyclopropyl)-{4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidine-1-carbonyl}-cyclopropanecarbonitrile;(1-methylcyclopropyl)-{4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;((S)-2,2-dimethyl-cyclopropyl)-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;(2,2-dimethylcyclopropyl)-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;[4-[4-[8-(4-methylpiperazin-1-yl)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;[4-[4-(8-amino-7-quinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;{4-[4-(8-methylaminoquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{4-[4-(8-methylaminoquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;(4-{4-[8-(2-methoxyethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone;1-(4-{4-[8-(2-methoxyethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one;(4-{4-[8-(2-dimethylaminoethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone;7-[4-(1-propionyl-piperidin-4-yloxy)-phenyl]-quinoline-8-carbonitrile;[4-[4-[8-(dimethylamino)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;1-{4-[4-(8-dimethylaminoquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{4-[4-(8-dimethylaminoquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;(4-{4-[8-(2-pyrrolidin-1-yl-ethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone;1-(4-{4-[8-(2-pyrrolidin-1-yl-ethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one;7-[4-[[1-[(2R)-tetrahydrofuran-2-carbonyl]-4piperidyl]oxy]phenyl]quinoline-8-carboxamide;7-[4-(1-propionyl-piperidin-4-yloxy)-phenyl]-quinoline-8-carboxylic acidamide; (S)-1-(3-(4-(quinolin-7-yl)phenoxy)pyrrolidin-1-yl)propan-1-one;(R)-1-(3-(4-(quinolin-7-yl)phenoxy)pyrrolidin-1-yl)propan-1-one;1-(4-(4-(5-methylquinolin-7-yl)phenoxy)piperidin-1-yl)propan-1-one;cyclopropyl(4-(4-(5-methylquinolin-7-yl)phenoxy)piperidin-1-yl)methanone;(R)-(4-(4-(5-methyl-quinolin-7-yl)phenoxy)piperidin-1-yl)(tetrahydrofuran-2-yl)methanone;(±)-(7S,8aS)-7-(4-(8-methylquinolin-7-yl)phenoxy)hexahydroindolizin-3(2H)-one;(±)-(7R,8aS)-7-(4-(8-methylquinolin-7-yl)phenoxy)hexahydroindolizin-3(2H)-one;2,2,2-trifluoro-1-{4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-ethanone;2,2-difluoro-1-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;2-fluoro-1-{4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;{cis-3-fluoro-4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{cis-3-fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{cis-3-fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{(trans)-3-fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;1-{trans-3-fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{trans-3-fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;1-{3-methyl-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one;cyclopropyl-{3-methyl-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{3-methyl-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;[4-[4-(8-cyclopropyl-7-quinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone;1-(4-((4-(quinolin-7-yl)phenyl)thio)piperidin-1-yl)propan-1-one;1-(4-((4-(isoquinolin-6-yl)phenyl)thio)-piperidin-1-yl)propan-1-one; andsalts thereof, e.g., pharmaceutically acceptable salts.

Additional compounds according to Formula IV may include for example:N-ethyl-4-[4-(2-hydroxy-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-pyrrolidin-1-ylethyl)piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-morpholinoethyl)piperidine-1-carboxamide;(4-isopropylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;(4-methylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(4-morpholino-1-piperidyl)methanone;(4-ethylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanonetosylate;N-(cyclopropylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]-piperidine-1-carboxamide;N-(2-methoxyethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isobutoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-(2-dimethylaminoethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-[2-(1H-imidazol-4-yl)ethyl]-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-tetrahydropyran-4-yl-piperidine-1-carboxamide;N-cyclobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-piperidine-1-carbohydroxamic acid;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(oxazinan-2-yl)methanone;N-(cyclobutylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;azepan-1-yl-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide;2-amino-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]ethanone;(2R)-2-amino-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]propan-1-one;(2S)-2-amino-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]propan-1-one;2-(dimethylamino)-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]ethanone;[(2R)-1-methylpyrrolidin-2-yl]-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;[(2S)-1-methylpyrrolidin-2-yl]-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;S-isopropyl 4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbothioate;2-amino-2-methyl-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-propan-1-one;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-[(2R)-pyrrolidin-2-yl]methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-[(2S)-pyrrolidin-2-yl]methanone;[1-(methylamino)cyclopropyl]-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;3-amino-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]propan-1-one;2-isopropoxy-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]ethanone;[2-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-2-oxo-ethyl]acetate;2-hydroxy-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]ethanone;(1-aminocyclobutyl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-methanone;N-ethyl-4-[4-(2-fluoro-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamideand salts thereof, e.g., pharmaceutically acceptable salts thereof.

Compounds according to Formula V or V(a) may include for example:isoxazolidin-2-yl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;[4-(4-isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-isoxazolidin-2-yl-methanone;isoxazolidin-2-yl-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(4-chloro-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-isoxazolidin-2-yl-methanone;{4-[4-(8-chloro-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-isoxazolidin-2-yl-methanone;isoxazolidin-2-yl-{4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-{4-[4-(7-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-[4-(4-quinoxalin-2-yl-phenoxy)-piperidin-1-yl]-methanone;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidmethoxyamide;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidmethoxymethylamide;4-[4-(4-methylquinolin-3-yl)-phenoxy]piperidine-1-carboxylic acidethylamide;4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidmethylamide;4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidethylamide; 4-[4-(4-methylquinolin-3-yl)-phenoxy]piperidine-1-carboxylicacid hydroxyamide;N-ethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N,N-dimethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-methoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-ethoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-pyrrolidin-1-yl-methanone;N-methyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-propylpiperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(1-piperidyl)methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-morpholinomethanone;N-methoxy-4-[4-(8-methoxy-7-quinolyl)phenoxy]piperidine-1-carboxamide;3-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-oxazolidin-2-one;1-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-pyrrolidin-2-one;and salts thereof, e.g., pharmaceutically acceptable salts thereof.

Additional compounds according to Formula V may include for example:N-ethyl-4-[4-(2-hydroxy-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-pyrrolidin-1-ylethyl)piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-morpholinoethyl)piperidine-1-carboxamide;(4-isopropylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;(4-methylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(4-morpholino-1-piperidyl)methanone;(4-ethylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;N-ethyl-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-ethoxyoxy-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-methoxyoxy-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-(cyclopropylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]-piperidine-1-carboxamide;N-isobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-(2-methoxyethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isobutoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-(2-dimethylaminoethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-[2-(1H-imidazol-4-yl)ethyl]-4-[4-(8-methyl-7-quinolyl)phenoxy]-piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-tetrahydropyran-4-yl-piperidine-1-carboxamide;N-cyclobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbohydroxamic acid;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(oxazinan-2-yl)-methanone;N-(cyclobutylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;azepan-1-yl-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;N-butyl-4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-ethyl-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-isobutyl-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-propyl-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-(2-methoxyethyl)-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-(cyclopropyl-methyl)piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-isopropoxy-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-isopropyl-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-isobutoxy-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-isopentyl-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-ethoxy-piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carbohydroxamicacid;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-propoxy-piperidine-1-carboxamide;4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-ethyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;N-isobutyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-(cyclopropylmethyl)-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]-N-propoxypiperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carbohydroxamic acid;N-ethoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-ethoxy-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide;N-isobutyl-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;N-ethyl-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-isobutyl-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-propyl-piperidine-1-carboxamide;N-(cyclopropylmethyl)-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]piperidine-1-carboxamide;4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-(3-pyridyl)-piperidine-1-carboxamide;N-(2-methoxyethyl)-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-piperidine-1-carboxamide;[4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-1-piperidyl]-(4-methylpiperazin-1-yl)methanone;N,N-dimethyl-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-isobutoxy-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-isopropyl-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-piperidine-1-carboxamide;4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-(1-methylpyrazol-4-yl)piperidine-1-carboxamide;4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-(2,2,2-trifluoro-ethyl)piperidine-1-carboxamide;4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-propoxy-piperidine-1-carboxamide;N-ethoxy-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-methoxy-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carbohydroxamicacid;4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;N-ethyl-4-(4-imidazo[1,2-a]pyridin-7-ylphenoxy)piperidine-1-carboxamide;N-ethyl-4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]-N-propyl-piperidine-1-carboxamide;N-isobutyl-4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]piperidine-1-carboxamide;N-isobutyl-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carbohydroxamicacid;N,N-dimethyl-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]lpiperidine-1-carboxamide;[4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]-1-piperidyl]-pyrrolidin-1-yl-methanone;[(3S)-3-fluoropyrrolidin-1-yl]-[4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]-1-piperidyl]methanone;[(3R)-3-fluoropyrrolidin-1-yl]-[4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]-1-piperidyl]methanone;4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]-N-methylsulfanyl-piperidine-1-carboxamide;N-ethylsulfanyl-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-methylsulfanyl-piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-ethylsulfanyl-piperidine-1-carboxamide;1-[4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carbonyl]pyrrolidin-2-one;1-[4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carbonyl]pyrrolidin-2-one;4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]-N-propylpiperidine-1-carboxamide;N-ethyl-4-[4-(2-fluoro-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamideand salts thereof, e.g., pharmaceutically acceptable salts thereof.

Additional compounds according to Formula V(a) may include, for example:N-ethyl-4-[4-(2-hydroxy-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-pyrrolidin-1-ylethyl)piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-morpholinoethyl)piperidine-1-carboxamide;(4-isopropylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;(4-methylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(4-morpholino-1-piperidyl)methanone;(4-ethylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;N-(cyclopropylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-(2-methoxyethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isobutoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-(2-dimethylaminoethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-[2-(1H-imidazol-4-yl)ethyl]-4-[4-(8-methyl-7-quinolyl)phenoxy]-piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-tetrahydropyran-4-yl-piperidine-1-carboxamide;N-cyclobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbohydroxamic acid;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(oxazinan-2-yl)methanone;N-(cyclobutylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;azepan-1-yl-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide;N-ethyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;N-isobutyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-(cyclopropylmethyl)-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]-N-propoxypiperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carbohydroxamic acid;N-ethoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-ethoxy-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide;N-isobutyl-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-methylsulfanyl-piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-ethylsulfanyl-piperidine-1-carboxamide,1-[4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carbonyl]pyrrolidin-2-one;N-ethyl-4-[4-(2-fluoro-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamideand salts thereof, e.g., pharmaceutically acceptable salts thereof.

The following terms and expressions have meanings as discussed below.

As used herein, the term “about” refers to a range of values from ±10%of a specified value. For example, the phrase “about 50” would beunderstood to include ±10% of 50, or from 45 to 55. The phrase “fromabout 10 to 100” includes ±10% of 10 and ±10% of 100, or from 9 to 110.

As used herein, a range of integer values in the form “x-y” or “x to y”,or “x through y”, includes the integers x and y, and includes all of theintegers between x and y. For example, the expressions “1-6”, or “1 to6” or “1 through 6” are intended to include the integers 1, 2, 3, 4, 5,and 6. Preferred embodiments include each individual integer in therange, as well as any subcombination of integers. For example, preferredintegers for the expression “1-6” can include 1, 2, 3, 4, 5, 6, 1-2,1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 2-6, etc.

The term “acyl” means a radical of the general formula —C(═O)—R, wherein—R is hydrogen or hydrocarbyl. Examples include, acetyl (—C(═O)CH₃),propionyl (—C(═O)CH₂CH₃), benzoyl (—C(═O)C₆H₅), and phenylacetyl(—C(═O)CH₂C₆H₅).

The term “alkyl”, by itself or as part of another substituent means, astraight, branched or cyclic chain hydrocarbon radical, including di-and multi-radicals, having the number of carbon atoms designated (i.e.C₁-C₆ designates an alkyl group having from one to six carbons), andincludes straight, branched chain or cyclic groups. Examples of alkylgroups include: methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, neopentyl, hexyl, cyclohexyl and cyclopropylmethyl.

The term “alkylene,” by itself or as part of another substituent means adivalent straight, branched or cyclic chain hydrocarbon radical havingthe stated number of carbon atoms. For example, —(C₁-C₃)-alkylene-CO₂H,would include, e.g., —CH₂CH₂CH₂—CO₂H, —CH₂CH(CH₃)—CO₂H, —C(CH₃)₂—CO₂H,-cyclopropyl-CO₂H, and —CH(CH₃)—CH₂—CO₂H.

The term “alkoxy,” employed alone or in combination with other termsmeans an alkyl group having the designated number of carbon atoms, asdefined above, connected to the rest of the molecule via an oxygen atom,such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy(isopropoxy)and the higher homologs and isomers.

The term “alkenyl,” employed alone or in combination with other terms,means a stable monounsaturated or di-unsaturated hydrocarbon radicalstraight chain, branched chain or cyclic hydrocarbon group having thestated number of carbon atoms. Examples include vinyl, propenyl(allyl),crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl,cyclopentenyl, cyclopentadienyl and the higher homologs and isomers. Adivalent radical derived from an alkene is exemplified by —CH═CH—CH₂—.

The term “amine” or “amino” refers to radicals of the general formula—NRR′, wherein R and R′ are independently selected from hydrogen and ahydrocarbyl radical, or wherein R and R′ combined form a heterocyle.Examples of amino groups include: —NH₂, methylamino, diethylamino,anilino, benzylamino, piperidin-1-yl, piperazin-1-yl and indolin-1-yl.

The term “carbamyl” means the group —C(═O)NRR′, wherein R and R′ areindependently selected from hydrogen and a hydrocarbyl radical, orwherein R and R′ combined form a heterocyle. Examples of carbamyl groupsinclude: —C(═O)NH₂ and —C(═O)N(CH₃)₂.

The term “cycloalkyl” refers to alkyl radicals that contain one or morerings, for example C₃ to C₁₀ cycloalkyl groups, e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, andoctahydro-1H-indenyl.

The term “heteroalkyl” by itself or in combination with another term,means a stable straight or branched chain radical consisting of thestated number of carbon atoms and one or two heteroatoms selected fromO, N, and S, and wherein the nitrogen and sulfur atoms may be optionallyoxidized and the nitrogen heteroatom may be optionally quaternized. Theheteroatom(s) may be placed at any position of the heteroalkyl group,including between the rest of the heteroalkyl group and the fragment towhich it is attached, as well as attached to the most distal carbon atomin the heteroalkyl group. Examples include: —O—CH₂—CH₂—CH₃,—CH₂—CH₂CH₂—OH, —CH₂—CH₂—NH—CH₃, —CH₂—S—CH₂—CH₃, and —CH₂CH₂—S(═O)—CH₃.Up to two heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃ (wherein either or both of the two consecutive heteroatomsmay also be oxidized S (SO or SO₂) or oxidized N (NO)).

The term “heteroalkenyl,” by itself or in combination with another term,means a stable straight or branched chain mono- or di-unsaturatedhydrocarbon radical consisting of the stated number of carbon atoms andone or two heteroatoms selected from O, N, and S, and wherein thenitrogen and sulfur atoms may optionally be oxidized and the nitrogenheteroatom may optionally be quaternized. Up to two heteroatoms may beplaced consecutively. Examples include —CH═CH—O—CH₃, —CH═CH—CH₂—OH,—CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, and —CH₂—CH═CH—CH₂—SH.

The term “hydroxyalkyl” refers to a subset of heteroalkyl groups that isan alkyl radical wherein one or more of the carbon atoms is substitutedwith hydroxy. Examples include —CH₂CH(OH)CH₃ and —CH₂CH₂OH.

The terms “halo” or “halogen” by themselves or as part of anothersubstituent mean, a fluorine, chlorine, bromine, or iodine atom.

The term “haloalkyl” refers to a C₁-C₆ alkyl group in which one or moreof the carbon atoms is substituted with one or more halogen atoms.Preferred haloalkyl groups are C₁-C₄ alkyl groups in which one or moreof the carbon atoms is substituted with one or more halogen atoms. Thealkyl group may be a straight, branched or cyclic alkyl group. Thehalogen atom is one or more of fluorine, chlorine, bromine and iodine.Examples of haloalkyl groups include, trifluoromethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl and 2-chloroethyl.

The term “sulfamyl” means the group —SO₂NRR′, wherein R and R′ areindependently selected from hydrogen or a hydrocarbyl radical, orwherein R and R′ combined form a heterocycle. Examples of sulfamylgroups include: —SO₂NH₂, —SO₂N(CH₃)₂, —SO₂(pyrrol-1-yl) and—SO₂NH(C₆H₅).

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (4n+2) delocalizedit (pi) electrons).

The term “aryl,” employed alone or in combination with other terms,means a carbocyclic aromatic system containing one or more rings(typically one, two or three rings) wherein such rings may be attachedtogether in a pendent manner, such as a biphenyl, or may be fused, suchas naphthalene. Examples include phenyl; anthracyl; and naphthyl.

The term “heterocycle” or “heterocyclyl” or “heterocyclic,” by itself oras part of another substituent means, an unsubstituted or substituted,stable, mono- or multicyclic heterocyclic ring system which consists ofcarbon atoms and at least one heteroatom selected from N, O, and S, andwherein the nitrogen and sulfur heteroatoms may be optionally oxidized,and the nitrogen atom may be optionally quaternized. The heterocyclicsystem may be attached, unless otherwise stated, at any heteroatom orcarbon atom which affords a stable structure.

As used herein “stable structure” or “stable compound” refers to acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture. The compounds according to thepresent invention are stable compounds.

The term “heteroaryl” or “heteroaromatic” refers to a heterocycle havingaromatic character.

Examples of non-aromatic heterocycles include monocyclic groups such as:Aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane,2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane,piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine,morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran,1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane,4,7-dihydro-1,3-dioxepin and hexamethyleneoxide.

Examples of heteroaryl groups include: Pyridyl, pyrazinyl, pyrimidinyl,particularly 2- and 4-pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl,particularly 2-pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl,particularly 3- and 5-pyrazolyl, isothiazolyl, 1,2,3-traizolyl,1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl,1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

Examples of polycyclic heterocycles include: bicyclic heterocycles, suchas, Indolyl, particularly 3-, 4-, 5-, 6- and 7-indolyl, indolinyl,quinolyl, tetrahydroquinolyl, isoquinolyl, particularly 1- and5-isoquinolyl, tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl,particularly 2- and 5-quinoxalinyl, quinazolinyl, 1,4-benzodioxanyl,coumarin, dihydrocoumarin, benzofuryl, particularly 3-, 4-, 5-, 6- and7-benzofuryl, 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl,particularly 3-, 4-, 5-, 6-, and 7-benzothienyl, benzoxazolyl,benzthiazolyl, particularly 2-benzothiazolyl and 5-benzothiazolyl,purinyl, benzimidazolyl, particularly 2-benzimidazolyl, benztriazolyl,thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, andquinolizidinyl. Polycyclic heterocycles also include tricyclic and otherpolycyclic heterocycles such as dibenzofuran andbenzofuro[2,3-b]pyridine.

The aforementioned listing of heterocyclyl and heteroaryl moieties isintended to be representative, not limiting.

The term “hydrocarbyl” refers to any moiety comprising only hydrogen andcarbon atoms. For example, the term (C₁-C₇)hydrocarbyl would includehydrocarbon groups such as (C₁-C₇)alkyl groups and cycloalkyl,(C₁-C₇)alkenyl and cycloalkenyl groups, (C₁-C₇)alkynyl and cycloalkynylgroups, and aryl, e.g., benzyl and tolyl groups.

As used herein, the term “substituted” refers in general to any one ormore hydrogen atoms on the indicated atom (preferably a carbon atom)being replaced with a selected group referred to herein as a“substituent”, provided that the substituted atom's valency is notexceeded, and that the substitution results in a stable compound. Asubstituted group has from 1 to 5, preferably 1 to 3, and morepreferably 1 independently selected substituents. Possible substituentsinclude, but are not limited to halogens, —OH, —OR, —NR₂, —NHOH, —NO₂,—CN, —CF₃, —CF₂CF₃, —C₁-C₇ hydrocarbyl, —C₁-C₆ alkoxy, 3-7-memberedheterocyclyl, 3-7-membered heteroaryl, ═O, ═S, —C(═O)R, —COOH, —CO₂R,—O—C(═O)R, —C(═O)NRR′, —NRC(═O)R′, —NRCO₂R′, —OC(═O)NRR′, —NRC(═O)NRR′,—NRC(═S)NRR′, and —SO₂NRR′, wherein R and R′ are each independently —H,—C₁-C₇ hydrocarbyl (e.g., —C₁-C₆ alkyl, —C₂-C₆ alkenyl —C₃-C₆cycloalkyl, benzyl, or phenyl) or (C₁-C₇)acyl.

Where a substituent is an alkyl or alkoxy group, the carbon chain may bebranched, straight or cyclic, with straight being preferred.

Accordingly, the term “substituted hydrocarbyl” refers to: a hydrocarbylgroup as defined above, having 1, 2, 3, 4 or 5 substituents,independently selected from the selection provided in the definition ofthe term “substituent” herein. Similarly, the expressions “substitutedalkyl,” “substituted cycloalkyl,” “substituted alkenyl,” “substitutedalkynyl,” “substituted aryl,” “substituted benzyl,” etc. refer to thespecified (e.g., alkyl) group as defined herein, having 1, 2, 3, 4 or 5substituents, independently selected from the selection provided in thedefinition of the term “substituent” herein.

As used herein, the term “subject” refers to a warm blooded animal suchas a mammal, preferably a human, which is afflicted with, or has thepotential to be afflicted with one or more diseases and conditionsdescribed herein.

As used herein, a “therapeutically effective amount” refers to an amountof a compound of the present invention that is effective to treat orprevent the symptoms of a particular disorder. Such disorders include,but are not limited to; those pathological and neurological disordersassociated with the aberrant activity of the receptors described herein,wherein the treatment or prevention comprises inhibiting the activitythereof by contacting the receptor with a compound of the presentinvention.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for contact withthe tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem complicationscommensurate with a reasonable benefit/risk ratio. The term“pharmaceutically acceptable salt” refers to salts of compounds of thepresent invention that may be derived from the combination of suchcompounds with non-toxic acid or base addition salts.

Acid addition salts include inorganic acids such as hydrochloric,hydrobromic, hydroiodic, sulfuric, nitric and phosphoric acid, as wellas organic acids such as acetic, citric, propionic, trifluoroacetic,tartaric, glutamic, salicylic, oxalic, methanesulfonic, benzenesulfonic,para-toluenesulfonic, succinic, and benzoic acid, and related inorganicand organic acids.

Base addition salts include those derived from inorganic bases such asammonium and alkali and alkaline earth metal hydroxides, carbonates, andbicarbonates, as well as salts derived from basic organic amines such asaliphatic and aromatic amines, aliphatic diamines, and hydroxyalkamines. Such bases useful in preparing the salts of this inventionthus include, for example, ammonium hydroxide, potassium carbonate,sodium bicarbonate, calcium hydroxide, methylamine, diethylamine,ethylenediamine, cyclohexylamine, diisopropylethyl amine (DIPEA),ethanolamine.

In addition to pharmaceutically-acceptable salts, other salts areincluded in the invention. They may serve as intermediates in thepurification of the compounds, in the preparation of other salts, or inthe identification and characterization of the compounds orintermediates.

The pharmaceutically acceptable salts of compounds of the presentinvention can also exist as various solvates, such as with water,methanol, ethanol, dimethylformamide, ethyl acetate and THF. Mixtures ofsuch solvates can also be prepared. The source of such solvate can befrom the solvent of crystallization, inherent in the solvent ofpreparation or crystallization, or adventitious to such solvent. Suchsolvates are within the scope of the present invention.

It will be understood that compounds of the present invention may existin various stereoisomeric forms. As such, the compounds of the presentinvention include both diastereomers and enantiomers. The compounds maybe prepared as racemates and can conveniently be used as such. However,individual enantiomers can be isolated by resolution or chiralseparation of a racemate, or may be synthesized by conventionaltechniques if so desired. Such racemates and individual enantiomers andmixtures thereof form part of the present invention.

It is known in the art how to prepare and isolate such optically activeforms. Specific stereoisomers can be prepared by stereospecificsynthesis using enantiomerically pure or enantiomerically enrichedstarting materials. The specific stereoisomers of either startingmaterials or products can be resolved and recovered by techniques knownin the art, such as resolution of racemic forms, normal, reverse-phase,chiral chromatography, recrystallization, enzymatic resolution, orfractional recrystallization of addition salts formed by reagents usedfor that purpose. Useful methods of resolving and recovering specificstereoisomers described in Eliel, E. L.; Wilen, S. H. Stereochemistry ofOrganic Compounds; Wiley: New York, 1994, and Jacques, J, et al.Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981.

It is further recognized that functional groups present on intermediatesused for the synthesis of the compounds of Formula I may containprotecting groups. For example, the amino acid side chain substituentsof the compounds of Formula I can be substituted with protecting groupssuch as benzyloxycarbonyl or t-butoxycarbonyl groups. Protecting groupsare known per se as chemical functional groups that can be selectivelyappended to and removed from functionalities, such as hydroxyl groupsand carboxyl groups. These groups are present in a chemical compound torender such functionality inert to chemical reaction conditions to whichthe compound is exposed. Any of a variety of protecting groups may beemployed with the present invention. Preferred groups for protectinglactams include silyl groups such as t-butyldimethylsilyl (“TBDMS”),dimethoxybenzhydryl (“DMB”), acyl, benzyl (“Bn”), methoxybenzyl, anddimethoxy (e.g., 2-4-dimethoxy) benzyl groups. Preferred groups forprotecting hydroxy groups include TBS, acyl, benzyl, benzyloxycarbonyl(“CBZ”), t-butyloxycarbonyl (“Boc”), and methoxymethyl. Many otherstandard protecting groups employed by one skilled in the art can befound in Greene, T. W. and Wuts, P. G. M., “Protective Groups in OrganicSynthesis” 2d. Ed., Wiley & Sons, 1991.

The compounds described herein are also intended to include suchcompounds wherein the molecular structures include isotopes of atoms inthe chemical structure, e.g., carbon, hydrogen, nitrogen sulfur, andother atoms occurring on those structures. Isotopes include those atomshaving the same atomic number but different mass numbers. For example,isotopes of hydrogen include deuterium; isotopes of carbon include ¹³C;isotopes of nitrogen include ¹⁵N; and isotopes of sulfur include ³³S.

Accordingly, within the chemical structure of any compound that istaught in this application:

-   -   any hydrogen atom or group of hydrogen atoms, e.g., in a        hydrocarbyl, heteroalkyl, aryl, heteroaryl, heterocyclyl or        carbocyclyl group, could suitably be replaced by an isotope of        hydrogen, i.e., deuterium;    -   any carbon atom or group of carbon atoms, e.g., in a        hydrocarbyl, heteroalkyl, aryl, heteroaryl, heterocyclyl or        carbocyclyl group, could suitably be replaced by an isotope of        carbon, e.g., ¹³C;    -   any nitrogen atom or group of nitrogen atoms, e.g., in a        heteroalkyl, heteroaryl, or heterocyclyl group, could suitably        be replaced by an isotope of nitrogen, e.g., ¹⁵N; and    -   any sulfur atom or group of sulfur atoms, e.g., in a        heteroalkyl, heteroaryl, or heterocyclyl group, could suitably        be replaced by an isotope of sulfur, e.g., ³³S.

As used herein, a compound that is termed “isotopically-enriched” meansthat the abundance, e.g., of deuterium, ¹³C, or ¹⁵N or ³³S at anyrelevant site of the compound is substantially more than the abundanceof deuterium, ¹³C, or ¹⁵N or ³³S naturally occurring at that site in anamount of the compound. A relevant site in a compound as used above is asite which would be designated as “H” or “C” or “N” or “S” in a chemicalstructure representation of the compound when not enriched. Relevantsites in the chemical structure of compounds taught herein for isotopicreplacement an atom or atoms can include any site that is syntheticallyaccessible for such isotopic replacement. The expression, “naturallyoccurring,” as used above refers to the abundance of the particular atomwhich would be present at a relevant site in a compound if the compoundwas prepared without any affirmative synthesis step to enrich theabundance of a different isotope.

Thus, for example in a “deuterium-enriched” compound, the abundance ofdeuterium at any relevant site in the chemical structure can range froman amount that is substantially more than the natural abundance ofdeuterium (about 0.0115%) up to 100%, for example, from about 1% toabout 100%, or from about 10% to about 100%, or from about 50% to about100%, or from about 90% to about 100%.

Similarly, for a “¹³C-enriched” compound, the abundance of ¹³C at anyrelevant site in the chemical structure of the compound can range froman amount that is substantially more than the natural abundance of ¹³C(about 1.109%) all the way up to 100%, for example, from about 5% toabout 100%, or from about 10% to about 100%, or from about 50% to about100%, or from about 90% to about 100%. Similarly for a “¹⁵N-enriched”compound, the abundance of ¹⁵N at any relevant site in the chemicalstructure of the compound can range from an amount that is substantiallymore than the natural abundance of ¹⁵N (about 0.364%) all the way up to100%, for example, from about 1% to about 100%, or from about 10% toabout 100%, or from about 50% to about 100%, or from about 90% to about100%.

Isotopically-enriched compounds can generally be prepared byconventional techniques known to those skilled in the art. Suchisotopically-enriched compounds can also be prepared by adaptingconventional processes as described in the scientific literature forsynthesis of compounds disclosed herein, and using an appropriateisotopically-substituted reagent (or reagents) in place of thecorresponding non isotopically-substituted reagent(s) employed in theconventional synthesis of the non isotopically-enriched compounds.Examples of ways to obtain a deuterium-enriched compound includeexchanging hydrogen with deuterium or synthesizing the compound withdeuterium-enriched starting materials.

As used herein, the term “unit dose” refers to a single dose which iscapable of being administered to a patient, and which can be readilyhandled and packaged, remaining as a physically and chemically stableunit dose comprising either the active compound itself, or as apharmaceutically acceptable composition, as described herein.

All other terms that are used herein in the description of the presentinvention will be understood to have meanings such as would beunderstood and accepted in the art.

For therapeutic purposes, the compounds that are described herein may beadministered to a subject by any means that results in the contact ofthe active agent with the agent's site of action in the body of thesubject. The compounds may be administered by any conventional meansavailable for use in conjunction with pharmaceuticals, either asindividual therapeutic agents, or in combination with other therapeuticagents. The compounds are preferably administered in therapeuticallyeffective amounts for the treatment of the diseases and disordersdescribed herein to a subject in need thereof.

A therapeutically effective amount of a compound as described herein maybe readily determined by an attending diagnostician, as one skilled inthe art, by the use of conventional techniques. The effective dose willvary depending upon a number of factors, including the type of diseaseor disorder treated, the extent of progression of the disease ordisorder, the overall health status of the subject to be treated, therelative biological efficacy of the compound selected, the formulationof the active agent, and the route of administration used in treatment.Typically, the compounds are initially administered at lower dosagelevels, with a gradual increase until the desired therapeutic effect isobtained.

Typical dose ranges may be from about 0.01 mg/kg to about 100 mg/kg ofbody weight per day, or from about 0.01 mg/kg to 10 mg/kg of body weightper day. Daily doses for adult humans may include about 25, 50, 100 and200 mg, and an equivalent dose in a human child. The compounds may beadministered in one or more unit dose forms. The unit dose may rangefrom about 1 to about 500 mg administered one to four times a day, e.g.,from about 10 mg to about 300 mg, administered two times a day. In analternate method of describing an effective dose, an oral unit dose isone that is necessary to achieve a therapeutic blood serum level, e.g.,a blood serum level of about 0.05 to 20 micrograms/mL in a subject, orabout 1 to 20 micrograms/mL. The compounds described herein may beadministered as the pure chemicals; however it is preferable toadminister the active ingredient as a pharmaceutical composition.

Generally, compounds described herein may be administered to a patientalone or in combination with a pharmaceutically acceptable carrier.Accordingly, the compounds of the invention, for example, compounds ofFormulae I-V(a), are preferably combined with a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice—as described, for example, in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa., 1980), thedisclosures of which are hereby incorporated herein by reference, intheir entireties. The carrier(s) must be acceptable in the sense ofbeing compatible with the other ingredients of the composition and notdeleterious to the subject. The relative proportions of activeingredient and carrier may be determined, for example, by the solubilityand chemical nature of the compounds, the chosen route of administrationand standard pharmaceutical practice.

The compounds described herein may be formulated into pharmaceuticalcompositions by admixture with one or more pharmaceutically acceptableexcipients. The excipients may be selected on the basis of the chosenroute of administration and standard pharmaceutical practice, asdescribed, for example, in Remington: The Science and Practice ofPharmacy, 20th ed.; Gennaro, A. R., Ed.; Lippincott Williams & Wilkins:Philadelphia, Pa., 2000. The compositions may be formulated to controland/or delay the release of the active agent(s), as in fast-dissolve,modified-release, or sustained-release formulations.

According to some embodiments of the invention, a pharmaceuticalcomposition herein may contain both an amount of a FASN inhibitor havinga chemical structure as described herein, and an amount of anantipsychotic agent. Suitable antipsychotic agents for such a dual APIpharmaceutical composition include, for example, clozapine, risperidone,aripiprazole, olanzapine, quetiapine and ziprasidone. Such a dual APIpharmaceutical composition may contain, for example, per dosage unit,from about 5 to about 1000 mg, or more, of a FASN inhibitor having achemical structure as described herein, and from about 5 to about 1000mg of an antipsychoric agent. In such embodiment, it is not necessarythat each single dosage unit include an effective amount so long as thetotal amount of drug administered to a patient is an effective amount ofeach. Therefore, for example, a patient may require two or more singledosage units to receive effective amounts of both agents. The dosage maybe adjusted appropriately to achieve desired drug levels, locally orsystemically of both drugs.

The compositions can be prepared for administration by oral means;parenteral means, including intravenous, intramuscular, and subcutaneousroutes; topical or transdermal means; transmucosal means, includingrectal, vaginal, sublingual and buccal routes; ophthalmic means; orinhalation means. Preferably the compositions are prepared for oraladministration, particularly in the form of tablets, capsules or syrups;for parenteral administration, particularly in the form of liquidsolutions, suspensions or emulsions; for intranasal administration,particularly in the form of powders, nasal drops, or aerosols; or fortopical administration, such as creams, ointments, solutions,suspensions aerosols, powders.

For oral administration, e.g., tablets, pills, powders, capsules, andtroches, formulations can contain one or more of the following: diluentsor fillers such as starch, or cellulose; binders such asmicrocrystalline cellulose, gelatins, or polyvinylpyrrolidones;disintegrants such as starch or cellulose derivatives; lubricants suchas talc or magnesium stearate; glidants such as colloidal silicondioxide; sweetening agents such as sucrose or saccharin; and flavoringagents such as peppermint or cherry flavoring. Capsules may contain anyof the excipients as listed above, and may additionally contain asemi-solid or liquid carrier, such as a polyethylene glycol. Solid oraldosage forms may have coatings of sugar, shellac, or enteric agents.Liquid preparations may be in the form of aqueous or oily suspensions,solutions, emulsions, syrups, elixirs, etc., or may be presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid preparations may contain conventional additivessuch as surfactants, suspending agents, emulsifying agents, diluents,sweetening and flavoring agents, dyes and preservatives.

The compositions may also be administered parenterally. Thepharmaceutical forms acceptable for injectable use include, for example,sterile aqueous solutions, or suspensions. Aqueous carriers include, forexample, mixtures of alcohols and water, and buffered media. Nonaqueoussolvents include, for example, alcohols and glycols, such as ethanol,and polyethylene glycols; oils, such as vegetable oils; fatty acids andfatty acid esters. Other components can be added including surfactants;such as hydroxypropylcellulose; isotonic agents, such as sodiumchloride; fluid and nutrient replenishers; electrolyte replenishers;agents which control the release of the active compounds, such asaluminum monostearate, and various co-polymers; and antibacterialagents, such as chlorobutanol, or phenol; buffers. The parenteralpreparations can be enclosed in ampules, disposable syringes or multipledose vials. Other potentially useful parenteral delivery systems for theactive compounds include ethylene-vinyl acetate copolymer particles,osmotic pumps, implantable infusion systems, and liposomes.

Other possible modes of administration include formulations forinhalation, which include such means as dry powder, aerosol, or drops.Formulations for topical use are in the form of an ointment, cream, orgel. Typically these forms include a carrier, such as petrolatum,lanolin, stearyl alcohol, polyethylene glycols, or their combinations,and either an emulsifying agent, such as sodium lauryl sulfate, or agelling agent, such as tragacanth. Formulations suitable for transdermaladministration can be presented as discrete patches, as in a reservoiror microreservoir system, adhesive diffusion-controlled system or amatrix dispersion-type system. Formulations for buccal administrationinclude, for example lozenges or pastilles and may also include aflavored base, such as sucrose or acacia, and other excipients such asglycocholate. Formulations suitable for rectal administration arepreferably presented as unit-dose suppositories, with a solid basedcarrier, such as cocoa butter, and may include a salicylate.

Pharmaceutical kits may comprise a therapeutically effective amount of atherapeutic compound as described herein, in one or more sterilecontainers are also within the ambit of the present invention.Sterilization of the container may be carried out using conventionalsterilization methodology well known to those skilled in the art. Thesterile containers of materials may comprise separate containers, or oneor more multi-part containers. The compound as described herein may beseparate, or may be combined into a single dosage form as describedabove. Such kits may further include, if desired, one or more of variousconventional pharmaceutical kit components, e.g., one or morepharmaceutically acceptable carriers, additional vials for mixing thecomponents, etc., as will be readily apparent to those skilled in theart. Instructions, either as inserts or as labels, indicating quantitiesof the components to be administered, guidelines for administration,and/or guidelines for mixing the components, may also be included insuch a kit.

The compounds of the present invention may be used in methods fortreating a condition or disorder associated with increased FASNexpression and/or activity. Such disorders include, for example:

obesity,

eating disorders

drug induced body weight gain; e.g. atypical antipsychotic-inducedweight gain

cardiovascular diseases,

gastrointestinal disorders,

dermatological disorders,

metabolic diseases (e.g., non-alcoholic hepatic steatosis (NASH)) andType 2 diabetes. (NASH is a serious liver disease for which thepathogenesis and prognosis have not been clearly determined. It isgenerally believed that abnormal fatty acid metabolism may be involvedin the pathogenesis of NASH, with triacylglycerols and their fatty acidprecursors likely possibly accumulating in the hepatocyte.)

viral disorders wherein FASN inhibition correlates inhibition of viralreplication, and

cancers and/or cancer metastasis (e.g., human breast, ovarian, prostate,colon, lung, bladder, stomach and kidney cancers).

The methods of treatment provided herein comprise administering to asubject in need of such treatment a therapeutically effective amount ofa compound of the invention, preferably a compound of Formulae I-V(a).Accordingly, the invention includes a method of treatment of a subjectsuffering from a disorder mediated by fatty acid synthase, comprisingadministering to the subject a therapeutically effective amount of acompound according to Formulae I, II, III, IV, V or V(a); or atherapeutically effective amount of a pharmaceutical compositioncomprising a compound according to Formulae I, II, III, IV, V or V(a).The invention also includes a method of treating a subject who issuffering from obesity, weight gain, or weight gain, or weight gainassociated with drug therapy, e.g., drug therapy with an antipsychoticagent, e.g., clozapine, risperidone, aripiprazole, olanzapine,quetiapine and ziprasidone. The method comprises administering to thesubject a therapeutically effective amount of a compound according toFormulae I, II, III, IV, V or V(a); or a therapeutically effectiveamount of a pharmaceutical composition comprising a compound accordingto Formulae I-V(a).

The compounds of the present invention can be synthesized using themethods as described generally herein, and by methods that are describedin the working examples that are provided herein, or variations thereon.The compounds of the invention may also be prepared by using other knownsynthetic methods, or variations thereon. Unless otherwise stated,starting compounds in the synthetic methods described herein arecommercially available, or may be readily synthesized by known methods.The reactions are generally performed in solvents that are appropriateto the reagents and reaction conditions. The materials employed in thereactions are understood to be suitable for the transformations beingeffected, and the materials and methods employed in product isolationunderstood to be suitable for the product compounds. Also, in thedescription of the synthetic methods herein, it is to be understood thatall proposed reaction conditions, including choice of solvent, reactionatmosphere, reaction temperature, duration of experiment and workupprocedures are chosen to be conditions appropriate for that reaction aswould be understood by one skilled in the art of organic synthesis. Itis understood that the examples and embodiments described herein areprovided for illustrative purposes only, and that various modificationsor changes in light thereof will be clearly understood to be includedwithin the scope of this application and the scope of the appendedclaims. Specific chemical transformations are listed in the schemes andworking examples provided herein, and the skilled person will readilyappreciate that a variety of different reagents may be used in place ofthose listed. Common replacements for such reagents can be found in, forexample, in texts such as “Encyclopedia of Reagents for OrganicSynthesis” Leo A. Paquette, John Wiley & Son Ltd (1995) or“Comprehensive 5 Organic Transformations: A Guide to Functional GroupPreparations” Richard C. Larock. Wiley-VCH and “Strategic Applicationsof Named Reactions in Organic Synthesis” Kurti and Czako, Elsevier, 2005and references therein.

Compounds according to Formula I-V(a) may be prepared by organicsyntheses utilizing known organic reactions. For example, Scheme 1below, outlines one of the general routes that was used to synthesizenumerous X=O examples of the invention. In Scheme 1, starting with acompound of formula 1 (for example, the known4-(4-iodophenoxy)piperidine-1-carboxylic acid tert-butyl ester 1, or4-(4-bromophenoxy)piperidine-1-carboxylic acid tert-butyl ester), atransition metal (e.g., palladium) catalyzed coupling reaction with anappropriate R⁶ boronic acid or R⁶ organostannane reagent can be used toproduce an intermediate of formula 2. The intermediate of formula 2 canthen be deprotected to remove the protecting group, PG (for example,under acidic conditions if the PG is a Boc group) to give anintermediate amine of formula 3. The intermediate amine of formula 3 maythen be reacted with reagents such as carboxylic acids, carboxylic acidhalides, carboxylic acid anhydrides, isocyanates, or sulfonyl halides toproduce compounds according to Formulae I-V(a).

Alternatively, the above order of the steps may be reversed, i.e., thestarting compound of formula 1 can be deprotected to produce anintermediate amine of formula 4. The intermediate amine of formula 4 maythen be reacted with reagents such as carboxylic acids, carboxylic acidhalides, carboxylic acid anhydrides, isocyanates, or sulfonyl halides toproduce an intermediate of formula 5. The intermediate amine of formula5 may then be reacted with an appropriate R⁶ boronic acid or R⁶organostannane reagent with transition metal (e.g., palladium) catalysisto produce compounds of Formulae I-V(a).

Other synthetic methodology can also be employed. For example,intermediates of formula 5 in Scheme 1 may also be synthesized using aMitsunobu reaction between an R⁵ substituted iodo- or bromophenol andN-substituted-hydroxypiperidine, as in Scheme 1a

Compounds of Formulae I-V(a) may also be synthesized (as shown in Scheme2 below) by reversing the functional groups on the coupling partnersshown in Scheme 1, for example starting with a boronate intermediate ofFormula 1a (for example,4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester). Palladium catalyzed coupling of a compound offormula 1 with bis(pinacolatato)diboron would provide such a boronateintermediate of formula 1a. The boronate intermediate 1a can be readilyconverted to R⁶ substituted compounds according to Formula I (orII-V(a)) by coupling an appropriate heteroaryl-halide or triflate;followed by deprotection of the piperidine nitrogen and acylation (orsulfonation) of the piperidine nitrogen, similar to the synthesis stepsdescribed in Scheme 1

Mitsunobu chemistry could also be used to produce intermediates offormula 1a, e.g., by reaction between an R⁵ substituted phenol boronateand an N-protected (or N-substituted) hydroxypiperidine, as in Scheme2a, below

The boronate intermediate 1a could also be synthesized in other ways,for example by, employing an SNAr reaction between a 4-fluoroiodobenzeneand a protected 4-hydroxy-piperidine of Formula 5d.

Compounds according to Formulae I-V(a), wherein the aromatic ringcontains one or two nitrogen ring atoms (e.g., pyridinyl and pyrimidinylring) may be synthesized from intermediates of formula 1H (heteroarylanalogs of compounds of formula 1) as outlined in Scheme 3 below usingMitsunobu reaction conditions.

For example, the Mitsunobu reaction to produce a pyridyl intermediate ofFormula 1H could be carried out between a 6-bromo-pyridin-3-ol and anN-protected-4-hydroxypiperidine (for example, Boc protected) as inScheme 3a below

Preparation of a heteroaryl (e.g., pyridyl or pyrimidyl) intermediate ofFormula 1H can of course be carried out in other ways, for example by,employing an SnAr reaction between a 2-chloropyridine or2-chloropyrimidine intermediate and an N-protected-4-hydroxypiperidine(for example, Boc protected) as in Scheme 3b below. Completion of thesynthesis of a compound of Formulae I-V(a) can be done by installationof an R⁶ aryl or heteroaryl group (e.g., via a Suzuki reaction),followed by deprotection of the piperidine nitrogen, and acylation (orsulfonylation) of the piperidine nitrogen, as described previously.

Examples of compounds of Formula I, II or III, where X=SO₂, X=NR⁹ andX=S may be synthesized using the same kinds of chemistry as has beendescribed previously for:

-   -   deprotection of the piperidine nitrogen;    -   acylation or sulfonation of the deprotected piperidine nitrogen;        and    -   transition metal (e.g., Pd) catalyzed coupling to install the        aromatic (or heteroaromatic) R⁶ group.

For compounds of Formula I, II or III, where X=SO₂, a suitable startingmaterial to use in place of the Formula 1 intermediate (in Scheme 1)would be an appropriately N-protected4-(4-bromobenzenesulfonyl)piperidine (or4-(4-iodobenzenesulfonyl)piperidine). Similarly, for compounds ofFormula I, II or II, where X=NR⁹, a suitable starting material to use inplace of the Formula 1 intermediate (in Scheme 1) would include, forexample, appropriately N-protected 4-(4-bromophenylamino)-piperidine (or4-(4-iodophenylamino)-piperidine) compounds.

For compounds of Formula I, II or III, where X=S, a suitable startingmaterial to use in place of the Formula 1 intermediate (in Scheme 1)would be an appropriately N-protected 4-(4-bromophenylsulfanyl)-piperidine or 4-(4-iodophenylsulfanyl)-piperidine. Suchsulfanyl intermediates could be prepared, for example, by converting thehydroxyl group of a N-protected-4-hydroxypiperidine intermediate offormula 5d to a leaving group (e.g., mesylate, tosylate, triflate, etc),and reacting with a 4-bromo- or 4-iodothiophenol, as shown in Scheme 4below.

FASN Enzyme activity may be determined by detecting coenzyme A (CoA), aproduct of FASN-catalyzed synthesis of palmitate from acetyl-CoA andmalonyl-CoA with NADPH as a cofactor. The assay is fluorescence-basedand measures the interaction of free CoA with7-diethylamino-3-(4′-malemimidylphenyl)-4-methylcoumarin (CPM; LifeTechnologies, CA) as described in Chung et al (2008). The coumarinderivative CPM contains a thiol-reactive maleimide that becomesfluorescent upon interaction with the sulfhydryl group of CoA.

For the example compounds described herein, the reaction was performedin 384-well low volume non-binding plates (Corning, N.Y.) usingrecombinant human baculovirus-expressed GST-tagged FASN. The 20-μL assaymixture contained 50 mM HEPES (pH 7.5), 5 nM FASN, 150 μM NADPH (Sigma,St. Louis, Mo.), 10 μM acetyl-CoA (Sigma), 25 μM malonyl-CoA (Sigma) andtest compound [diluted in dimethyl sulfoxide (DMSO); 0.5% DMSO final inassay after 100 nL addition]. See, Chung et al.; “A fluorescence-basedthiol quantification assay for ultra-high-throughput screening forinhibitors of coenzyme A production,” Assay Drug Dev Tech 2008;6:361-374.

The reaction was initiated by adding malonyl-CoA, followed by incubationfor 90 minutes at 250° C. A stock solution of the CPM reagent wasprepared in DMSO at 66 μM and stored at −200° C. To detect CoA producedin the FASN reaction, the CPM stock was diluted to 50 μM in 70% ethanoland added at 4 L/well to the assay plate. The reaction mixture was thenincubated for 30 minutes. Fluorescence was measured using the EnVision™2102 multi-label plate reader (PerkinElmer, Waltham, Mass.) utilizing ageneral dual mirror, a 390 nM excitation filter and a 530 nM emissionfilter. Data analysis was performed using ActivityBase (IDBS, Guilford,UK). IC₅₀ values were calculated by plotting the percent inhibitionversus log 10 of the concentration of the compound, and fitting to thenonlinear regression sigmoidal dose-response (variable slope) equationin XLFit (IDBS). The IC₅₀ data for the Examples described herein isprovided in Tables 2 and 2a below (A=1 to 99 nM; B=100 to 999 nM;C=1000-10,000 nM)

TABLE 2 IC₅₀ data for Compounds of Formulae I-V/V(a) Ex # Activity 1 A 2A 3 B 4 A 5 C 6 A 7 A 8 B 9 C 10 A 11 C 12 C 13 C 14 C 15 C 16 C 17 C 18B 19 C 20 C 21 C 22 A 23 A 24 A 25 C 26 C 27 C 28 A 29 A 30 A 31 A 32 B33 B 34 A 35 A 36 A 37 A 38 A 39 B 40 B 41 B 42 A 43 A 44 A 45 A 46 A 47A 48 A 49 A 50 B 51 C 52 C 53 C 54 B 55 C 56 C 57 B 58 B 59 A 60 A 61 A62 A 63 B 64 B 65 A 66 B 67 B 68 A 69 A 70 A 71 A 72 A 73 A 74 A 75 A 76A 77 A 78 A 79 A 80 A 81 A 82 A 83 A 84 A 85 B 86 A 87 C 88 A 89 A 90 B91 A 92 C 93 A 94 A 95 A 96 A 97 B 98 A 99 B 100 A 101 A 102 B 103 A 104A 105 A 106 B 107 C 108 B 109 C 110 C 111 C 112 B 113 B 114 B 115 B 116A 117 C 118 C 119 C 120 A 121 C 122 C 123 C 124 C 125 C 126 A 127 C 128C 129 C 130 C 131 A 132 C 133 C 134 C 135 B 136 C 137 B 138 C 139 C 140C 141 C 142 C 143 C 144 C 145 C 146 C 147 C 148 C 149 C 150 B 151 B 152A 153 C 154 A 155 C 156 B 157 C 158 C 159 C 160 C 161 C 162 C 163 B 164B 165 B 166 C 167 A 168 B 169 B 170 B 171 C 172 C 173 C 174 C 175 C 176C 177 C 178 B 179 B 180 A 181 A 182 B 183 C 184 B 185 B 186 A 187 A 188B 189 B 190 A 191 C 192 C 193 C 194 C 195 C 196 C 197 C 198 C 199 C 200A 201 NT 202 A 203 A 204 B 205 A 206 C 207 B 208 C 209 C 210 C 211 C 212C 213 C 214 C 215 B 216 C 217 B 218 C 219 A 220 A 221 A 222 A 223 A 224A 225 A 226 A 227 A 228 B 229 B 230 A 231 C 232 C 233 C 234 B 235 C 236B 237 C 238 B 239 C 240 C 241 C 242 C 243 C 244 A 245 B 246 C 247 B 248B 249 B 250 A 251 B 252 B 253 C 254 A 255 A 256 B 257 A 258 B 259 B 260A 261 A 262 A 263 A 264 C 265 A 266 B 267 A 268 C 269 B 270 B 271 B 272A 273 A 274 A 275 B 276 C 277 B 278 A 279 B 280 A 281 C 282 C 283 A 284C 285 A 286 C 287 B 288 B 289 C 290 C 291 C 292 B 293 C 294 C 295 A 296B 297 B 298 A 299 C 300 C 301 C 302 A 303 A 304 C 305 B 306 C 307 B 308C 309 A 310 C 311 A 312 B 313 C 314 C 315 C 316 A 317 A 318 A 319 C 320A 321 B 322 A 323 C 324 A 325 A 326 B 327 A 328 B 329 A 330 B 331 A 332C 333 C 334 B 335 C 336 B 337 C 338 B 339 C 340 C 341 C 342 C 343 C 344B 345 C 346 B 347 B 348 A 349 A 350 B 351 B 352 A 353 A 354 A 355 C 356C 357 C 358 B 359 A 360 B 361 C 362 A 363 B 364 B 365 C 366 A 367 C 368C 369 B 370 B 371 A 372 A 373 B 374 B 375 A 376 A 377 A 378 C 379 C 380C 381 B 382 C 383 C 384 C 385 C 386 C 387 C 388 C 389 C 390 C 391 C 392C 393 C 394 C 395 C 396 C 397 C 398 C 399 C 400 C 401 C 402 C 403 C 404C 405 C 406 C 407 C 408 C 409 C 410 B 411 B 412 A 413 C 414 C 415 C 416B 417 B 418 A 419 B 420 B 421 C 422 B 423 B 424 A 425 A 426 C 427 C 428B 429 A 430 C 431 A 432 A 433 B 434 B 435 B 436 A 437 A 438 A 439 C 440A 441 C 442 C 443 C 444 C 445 C 446 C 447 C 448 C 449 C 450 A 451 A 452A 453 B 454 A 455 C 456 A 457 A 458 A 459 A 460 B 461 B 462 A 463 C 464C 465 B 466 A 467 A 468 A 469 B 470 B 471 A 472 B 473 B 474 A 475 A 476A 477 A 478 A 479 A 480 A 481 A 482 A 483 A 484 B 485 A 486 A 487 A 488A 489 C 490 C 491 B 492 C 493 C 494 C 495 B 496 C 497 C 498 C 499 C 500C 501 C 502 C 503 C 504 C 505 C 506 C 507 C 508 C 509 C 510 C 511 C 512C 513 C 514 C 515 C 516 A 517 A 518 A 519 C 520 A 521 B 522 C 523 C 524B 525 B 526 C 527 C 528 B

TABLE 2a IC₅₀ data for Additional Compounds of Formulae I-V(a) Ex #Activity 529 C 530 A 531 C 532 C 533 C 534 C 535 C 536 C 537 A 538 A 539A 540 A 541 A 542 A 543 C 544 A 545 A 546 C 547 C 548 C 549 C 550 C 551C 552 C 553 C 554 C 555 C 556 C 557 C 558 C 559 A 560 B 561 C 562 C 563A 564 C 565 B 566 A 567 B 568 C 569 B 570 A 571 C 572 C 573 C 574 A 575A 576 C 577 B 578 C 579 B 580 A 581 A 582 C 583 A 584 A 585 B 586 C 587A 588 A 589 A 590 A 591 A 592 A 593 C 594 A 595 B 596 A 597 C 598 B 599C 600 B 601 A 602 C 603 C 604 C 605 C 606 C 607 C 608 B 609 A 610 C 611C 612 A 613 C 614 C 615 C 616 C 617 C 618 C 619 C 620 C 621 C 622 C 623C 624 C 625 A 626 A 627 C 628 A 629 C 630 B 631 A 632 A 633 A 634 NT 635NT 636 NT 637 NT 638 NT 639 NT 640 NT 641 NT 642 NT 643 NT 644 NT 645 NT646 NT 647 NT

EXAMPLES Example 1.1-[4-(4-Isoquinolin-6-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Step 1. 1-[4-(4-Bromophenoxy)-piperidin-1-yl]-propan-1-one

4-(4-Bromophenoxy)piperidine (1.0 g, 3.9 mmol) andN,N-diisopropylethylamine (DIPEA) (2.72 mL, 15.6 mmol) intetrahydrofuran (THF) (10 mL) was added propanoyl chloride (0.679 mL,7.81 mmol). After 2 h stirring at rt, the mixture was concentrated, theproduct suspended in EtOAc, and washed with 1N Na₂CO₃, water and brineand then dried (MgSO₄). The product was chromatographed on ISCO (80 gsilica gel column, 30-90% EtOAc/hexanes) to give a viscous oil. LCMSm/z=313 (M+1); ¹H NMR (CDCl₃) δ: 7.37 (d, 2H, J=7 Hz), 6.79 (d, 2H, J=7Hz), 4.49 (q, 1H, J=3 Hz), 3.74-3.80 (m, 1H), 3.59-3.71 (m, 2H),3.36-3.42 (m, 1H), 2.36 (q, 2H, J=7.5 Hz), 1.87-1.94 (m, 2H), 1.73-1.84(m, 2H), 1.16 (t, 3H, J=7.5 Hz).

Step 2. 1-[4-(4-Isoquinolin-6-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Palladium acetate (0.00719 g, 0.0320 mmol) and triphenylphosphine(0.0336 g, 0.128 mmol) in dioxane (5 mL) were stirred 15 min under anatmosphere of nitrogen. 1-[4-(4-bromophenoxy)piperidin-1-yl]propan-1-one(0.20 g, 0.646 mmol), isoquinoline-6-boronic acid (0.122 g, 0.705 mmol),N,N-dimethylformamide (DMF) (3 mL) and 1M sodium carbonate (2.56 mL)were added and heated at 80° C. for 17 h. The mixture was concentrated,was dissolved in EtOAc, washed with 1N Na₂CO₃, water and brine, thendried over MgSO₄. The product was purified by ISCO (12 g silica gelcolumn, 5% MeOH/EtOAc) to give an oil. The HCl salt was synthesized byadding 0.25 mL of 1M HCl-ether solution to a dichloromethane (DCM)solution of base. The salt was recrystallized from DCM-ether and driedto give a light yellow solid (125 mg, 54%). Analysis: LCMS m/z=361(M+1); ¹H NMR (DMSO-d₆ (deuterated dimethylsulfoxide)) δ: 9.72 (s, 1H),8.63 (d, 1H, J=6.5 Hz), 8.56 (s, 1H), 8.52 (d, 1H, J=8 Hz), 8.39 (d, 1H,J=6.5 Hz), 8.33 (dd, 1H, J=2, 8 Hz), 7.92 (d, 2H, J=8 Hz), 7.21 (d, 2H,J=8 Hz), 4.76 (q, 1H, J=4 Hz), 3.89 (m, 1H), 3.72 (m, 1H), 3.34-3.40 (m,1H), 3.25-3.31 (m, 1H), 2.35 (q, 2H, J=7.5 Hz), 1.99 (b, 2H), 1.63-1.67(m, 1H), 1.54 (m, 1H), 1.00 (t, 3H, J=7.5 Hz).

Example 2. 1-[4-(4-Quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one

This compound was synthesized using the previous method with1-[4-(4-bromo-phenoxy)-piperidin-1-yl]propan-1-one (0.150 g, 0.480mmol), and 3-quinolineboronic acid (0.1247 g, 0.7207 mmol) (120 mg,69%). Analysis: LCMS m/z=361 (m+1); ¹H NMR (CDCl₃) δ: 9.16 (s, 1H), 8.24(d, 1H, J=2 Hz), 8.10 (d, 1H, J=8 Hz), 7.86 (d, 1H, J=8 Hz), 7.68-7.73(m, 1H), 7.66 (d, 2H, J=8 Hz), 7.55-7.59 (m, 1H), 7.07 (d, 2H, J=8 Hz),4.63 (q, 1H, J=4 Hz), 3.79-3.85 (m, 1H), 3.65-3.76 (m, 2H), 3.41-3.47(m, 1H), 2.38 (q, 2H, J=7.5 Hz), 1.95-1.98 (b, 2H), 1.84-1.90 (b, 2H),1.17 (t, 3H, J=7.5 Hz).

Example 3.2-Methyl-1-[4-(4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Step 1. 7-[4-(Piperidin-4-yloxy)-phenyl]-quinoline dihydrochloride

Palladium acetate (0.0278 g, 0.124 mmol) and triphenylphosphine (0.130g, 0.496 mmol) in dioxane (10 mL) were stirred 15 min under anatmosphere of nitrogen. 4-(4-iodophenoxy)-piperidine-1-carboxylic acidtert-butyl ester (1.00 g, 2.48 mmol), quinoline-7-boronic acid (0.5147g, 2.976 mmol), DMF (10 mL) and 1 M sodium carbonate (9.92 mL) wereadded and heated at 80° C. for 18 h. The mixture was concentrated,dissolved in EtOAc, washed with 1N Na₂CO₃, water and brine, and thendried (MgSO₄). The Boc intermediate was purified by ISCO (silica gel, 80g; 40-80% EtOAc/hex) to give a white solid. This material was added 6 MHCl (10 mL) and heated at 65° C. for 4 h, then concentrated. The HClsalt was triturated with ether, dried and collected to give a yellowsolid. LCMS m/z=305 (M+1).

Step 2.2-Methyl-1-[4-(4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-propan-1-one

7-[4-(Piperidin-4-yloxy)-phenyl]-quinoline dihydrochloride (0.042 g,0.14 mmol) and DIPEA (0.097 mL, 0.55 mmol) in THF (2 mL) was addedisobutyryl chloride (0.029 mL, 0.28 mmol). After 4 h stirring at rt, themixture was concentrated, diluted with EtOAc and washed with 1N Na₂CO₃,water and brine, then dried (MgSO₄). The product was purified by ISCO (4g silica gel, 0-5% MeOH/DCM). The HCl salt was made from 2N HCl etherand was recrystallized from DCM-ether to give a white solid (40 mg,77%). Analysis: LCMS m/z=375 (M+1); ¹H NMR (DMSO-d6, HCl salt) δ: 9.21(d, 1H, J=4 Hz), 8.96 (d, 1H, J=8 Hz), 8.45 (s, 1H), 8.32 (d, 1H, J=8.3Hz), 8.21 (d, 1H, J=8.3 Hz), 7.89-7.92 (m, 1H), 7.83 (d, 2H, J=8 Hz),7.20 (d, 2H, J=8 Hz), 4.75 (m, 1H), 3.89 (b, 1H), 3.78 (b, 1H), 3.39 (b,1H), 3.27 (b, 1H), 3.90 (q, 1H, J=7 Hz), 1.95-2.01 (b, 2H), 1.63 (b,1H), 1.55 (b, 1H), 1.01 (d, 6H, J=7 Hz).

Example 4. 1-[4-(4-Quinolin-7-yl-phenoxy)-piperidin-1-yl]-propan-1-one

This compound was synthesized using the method for Example 3. Analysis:LCMS m/z=361 (M+1); ¹H NMR (DMSO-d6, HCl salt) δ: 9.17 (m, 1H), 8.92 (d,1H, J=8 Hz), 8.40 (s, 1H), 8.30 (d, 1H, J=9 Hz), 8.20 (dd, 1H, J=2, 8.5Hz), 8.86-8.90 (m, 1H), 8.63 (d, 1H, J=8.5 Hz), 7.20 (d, 2H, J=8.5 Hz),4.74 (q, 1H, J=4 Hz), 3.89 (m, 1H), 3.73 (m, 1H), 3.33-3.39 (m, 1H),3.24-3.29 (m, 1H), 2.34 (q, 2H, J=7.5 Hz), 1.90-2.03 (b, 2H), 1.61-1.65(m, 1H), 1.53-1.57 (m, 1H), 1.00 (t, 3H, J=7.5 Hz).

Example 5. 4-(2-Fluoro-4-quinolin-3-yl-phenox)piperidine-1-carboxylicacid t-butyl ester

Step a. 4-(4-Bromo-2-fluorophenoxy)piperidine-1-carboxylic acidtert-butyl ester

Triphenylphosphine (4.12 g, 15.71 mmol) in THF was added 6 M of diethylazodicarboxylate (DEAD) in toluene (2.62 mL, 15.71 mmol) at 0° C. After0.5 h, 4-bromo-2-fluoro-phenol (1.13 mL, 10.5 mmol) and4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.63 g, 13.09mmol) in THF (10 mL) was added dropwise and stirred for 18 h at rt. Themixture was filtered and concentrated. The product was dissolved in Et₂O(ca. 100 mL) and hexane (ca. 25 mL) and filtered. The ether wasconcentrated and the product purified by ISCO silica gel chromatography(120 g column; 15-20% EtOAc/hexanes) to give a solid (11 g, 82%).Analysis: LCMS m/z=375 (M+1); ¹H NMR (CDCl₃) δ 7.23-7.26 (m, 1H),7.11-7.21 (m, 1H), 6.84-6.92 (m, 1H), 4.41 (tt, J=7.0, 3.5 Hz, 1H),3.65-3.75 (m, 2H), 3.33 (ddd, J=13.5, 7.6, 4.0 Hz, 2H), 1.86-1.95 (m,2H), 1.69-1.82 (m, 3H), 1.44-1.48 (m, 9H).

Step b. 4-(2-Fluoro-4-quinolin-3-yl-phenox)piperidine-1-carboxylic acidtert-butyl ester

This compound was synthesized by the method for Example 3 using4-(4-bromo-2-fluoro-phenoxy)piperidine-1-carboxylic acid tert-butylester (0.50 g, 1.34 mmol), and 3-quinolineboronic acid (0.28 g, 1.60mmol). Analysis: LCMS m/z=423 (M+1); ¹H NMR (CDCl₃) 9.13 (d, 1H, J=2Hz), 8.12 (d, 1H, J=8.4 Hz), 7.87 (d, 1H, J=8.4 Hz), 7.64-7.74 (m, 2H),7.56-7.60 (m, 1H), 7.44-7.48 (m, 2H), 7.40-7.43 (m, 1H), 7.14 (t, 1H,J=8 Hz), 4.54 (q, 1H, J=4.5 Hz), 3.72-3.79 (m, 2H), 3.33-3.40 (m, 2H),1.94-2.00 (m, 2H), 1.79-1.87 (m, 2H), 1.48 (s, 9H).

Example 6.1-[4-(2-Fluoro-4-quinolin-3-yl-phenoxy)piperidin-1-yl]propan-1-one

Step 1. 3-[3-Fluoro-4-(piperidin-4-yloxy)-phenyl]-quinoline

4-(2-Fluoro-4-quinolin-3-yl-phenox)piperidine-1-carboxylic acidtert-butyl ester (0.5 g) was added 6M HCl (10 mL) and heated at 65° C.,then concentrated and the residue triturated with ether to give a lightyellow solid (350 mg, 82%). Analysis: LCMS m/z=323 (M+1); ¹H NMR(DMSO-d₆ HCl salt) δ: 9.49 (s, 1H), 9.11 (b, 3H), 8.25 (d, 1H, J=8 Hz),8.20 (d, 1H, J=8 Hz), 7.94-7.98 (m, 2H), 7.79-7.84 (m, 2H), 7.50 (t, 1H,J=8.5 Hz), 4.81 (b, 1H), 3.23 (b, 2H), 3.11 (b, 2H), 2.16 (b, 2H), 1.92(b, 2H).

Step 2.1-[4-(2-Fluoro-4-quinolin-3-yl-phenoxy)piperidin-1-yl]propan-1-one

3-[3-Fluoro-4-(piperidin-4-yloxy)phenyl]quinoline (0.070 g, 0.22 mmol)and DIPEA (0.113 mL, 0.651 mmol) in DCM (3 mL) was added propanoylchloride (0.0377 mL, 0.434 mmol). After 2 h stirring at rt the mixturewas concentrated, dissolved in EtOAc and washed with 1N Na₂CO₃ and brinethen dried over MgSO₄. The product was purified by ISCO (4 g silica gelcolumn, 0-5% MeOH/DCM) to give an oil. The HCl salt was made by adding0.25 mL 1N HCl-ether to a DCM solution of the base to give a yellowsolid (60 mg, 73%). Analysis: LCMS m/z=379 (M+1); ¹H NMR (DMSO-d₆ HClsalt) δ: 9.45 (s, 1H), 9.03 (s, 1H), 8.18 (t, 2H, J=7 Hz), 7.91-7.94 (m,2H), 7.75-7.81 (m, 2H), 7.48 (t, 1H, J=8 Hz), 4.77 (q, 1H, J=4 Hz), 3.78(b, 1H), 3.70 (b, 1H), 3.27-3.39 (m, 2H), 2.34 (q, 2H, J=7 Hz),1.93-1.99 (b, 2H), 1.66 (b, 1H), 1.57 (b, 1H), 1.00 (t, 3H, J=7 Hz).

Example 7.1-[4-(2-Fluoro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one

Analysis: LCMS m/z=393 (M+1); ¹H NMR (DMSO HCl salt) δ: 9.49 (s, 1H),9.09 (s, 1H), 9.19-9.24 (m, 2H), 7.92-7.97 (m, 2H), 7.77-7.84 (m, 2H),7.49 (t, 1H, J=8 Hz), 4.79 (q, 1H, J=4 Hz), 3.87 (b, 1H), 3.78 (b, 1H),3.40 (b, 1H), 3.29 (b, 1H), 2.91 (q, 1H, J=7 Hz), 2.00 (b, 1H), 1.96 (b,1H), 1.66 (b, 1H), 1.58 (b, 1H), 1.00 (d, 6H, J=7 Hz).

The following examples were synthesized starting with4-(4-bromophenoxy)-piperidine-1-carboxylic acid t-butyl ester or4-(4-iodophenoxy)piperidine-1-carboxylic acid t-butyl ester and anappropriate boronic acid using methods described for previous examples.

Example 8. 1-[4-(4-Benzofuran-5-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=350 (M+1); ¹H NMR (CDCl₃) δ: 7.70 (d, 1H, J=2 Hz),7.64 (d, 1H, J=2 Hz), 7.51-7.54 (m, 3H), 7.46 (dd, 1H, J=2, 8 Hz), 7.00(d, 2H, J=8.5 Hz), 6.80 (d, 1H, J=2 Hz), 4.58 (q, 1H, J=4 Hz), 3.79-3.85(m, 1H), 3.63-3.74 (m, 2H), 3.39-3.46 (m, 1H), 2.38 (q, 2H, J=7.5 Hz),1.94 (b, 2H), 1.84 (b, 2H), 1.17 (t, 3H, J=7.5 Hz).

Example 9.1-[4-(4-Benzofuran-5-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one

Analysis: LCMS m/z=364 (M+1); ¹H NMR (CDCl₃) δ: 7.73 (d, 1H, J=2 Hz),7.64 (d, 1H, J=2 Hz), 7.52-7.54 (m, 3H), 7.48 (d, 1H, J=2, 8 Hz), 7.00(d, 2H, J=8.5 Hz), 6.80 (m, 1H), 4.59 (q, 1H, J=4 Hz), 3.75-3.85 (m,2H), 3.64-3.68 (m, 1H), 3.47 (b, 1H), 2.84 (q, 1H, J=7 Hz), 1.96 (b,2H), 1.86 (b, 2H), 1.15 (d, 6H, J=7 Hz).

Example 10.1-[4-(4-Naphthalen-2-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=360 (M+1); ¹H NMR (CDCl₃) δ: 7.98 (s, 1H), 7.83-7.98(m, 3H), 7.70 (dd, 1H, J=2, 8.5 Hz), 7.64-7.67 (m, 2H), 7.44-7.51 (m,2H), 7.02-7.04 (m, 2H), 4.61 (q, 1H, J=4 Hz), 3.79-3.85 (m, 1H),3.64-3.76 (m, 2H), 3.40-3.46 (m, 1H), 2.37 (q, 2H, J=7 Hz), 1.92-1.97(m, 2H), 1.82-1.91 (m, 2H), 1.17 (t, 3H, J=7 Hz).

Example 11.2-Methyl-1-[4-(4-naphthalen-2-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=374 (M+1); ¹H NMR (CDCl₃) 7.98 (s, 1H), 7.84-7.90 (m,3H), 7.70 (dd, 1H, J=2, 8 Hz), 7.64-7.67 (m, 2H), 7.44-7.51 (m, 2H),7.02-7.05 (m, 2H), 4.61 (q, 1H, J=4 Hz), 3.75-3.85 (m, 2H), 1.65-1.72(m, 1H), 3.48 (b, 1H), 2.84 (q, 1H, J=7 Hz), 1.96 (b, 2H), 1.87 (b, 2H),1.15 (d, 6H, J=7 Hz).

Example 12.1-[4-(4-1,5-Naphthyridin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=362 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ: 9.42 (d, 1H,J=2 Hz), 9.10 (dd, 1H, J=2, 4 Hz), 8.67 (d, 1H, J=2 Hz), 8.57 (d, 1H,J=8.6 Hz), 7.91 (d, 2H, J=8.5 Hz), 7.85 (dd, 1H, J=2, 8 Hz), 7.20 (d,2H, J=8.5 Hz), 4.75 (q, 1H, J=4 Hz), 3.89 (m, 1H), 3.71 (m, 1H),3.33-3.39 (m, 1H), 3.24-3.30 (m, 1H), 2.34 (q, 2H, J=7 Hz), 1.98 (b,2H), 1.61-1.65 (m, 1H), 1.53-1.58 (m, 1H), 1.00 (t, 3H, J=7 Hz).

Example 13.2-Methyl-1-[4-(4-1,5-naphthyridin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=376 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ: 9.47 (d, 1H,J=2 Hz), 9.10 (dd, 1H, J=2, 4 Hz), 8.73 (d, 1H, J=2 Hz), 8.64 (d, 1H,J=8.5 Hz), 7.94 (d, 2H, J=8 Hz), 7.89-7.93 (m, 1H), 7.20 (d, 2H, J=8Hz), 4.76 (q, 1H, J=4 Hz), 3.89 (b, 1H), 3.78 (b, 1H), 3.35-3.44 (m,1H), 3.25-3.33 (m, 1H), 2.90 (q, 1H, J=6 Hz), 1.98 (b, 2H), 1.63 (b,1H), 1.55 (b, 1H), 1.00 (d, 6H, J=6 Hz).

Example 14.Cyclopropyl-[4-(4-1,5-naphthyridin-3-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS m/z=374 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ:9.40 (d, 1H,J=2 Hz), 9.06 (m, 1H), 9.63 (d, 1H, J=2 Hz), 8.51 (d, 1H, J=8.5 Hz),7.91 9d, 2H, J=8 Hz), 7.80-7.84 (dd, 1H, J=2, 4 Hz), 7.19 (d, 2H, J=8Hz), 4.77 (q, 1H, J=4 Hz), 4.00 (b, 1H), 3.90 (b, 1H), 3.57 (b, 1H),3.29 (b, 1H), 1.91-2.10 (m, 3H), 1.66 (b, 1H), 1.56 (b, 1H), 0.69-0.74(m, 4H).

Example 15. 4-(2-Fluoro-4-quinolin-3-yl-phenoxy)-piperidine-1-carboxylicacid methyl ester

Analysis: LCMS m/z=381 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ: 9.36 (s, 1H),8.86 (s, 1H), 8.10 (d, 2H, J=8 Hz), 7.83-7.90 (m, 2H), 7.71 (m, 2H),7.45 (t, 1H, J=9 Hz), 4.73 (m, 1H), 3.69-3.73 (m, 2H), 3.61 (s, 3H),3.27-3.32 (m, 2H), 1.96 (m, 2H), 1.59-1.65 (m, 2H).

Example 16.1-{4-[4-(2-Chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=395 (M+1); ¹H NMR (CDCl₃) δ: 8.09 (s, 1H), 8.05 (d,1H, J=8 Hz), 7.82 (d, 1H, J=8 Hz), 7.74 (t, 1H, J=7.5 Hz), 7.58 (t, 1H,J=7.5 Hz), 7.46 (d, 2H, J=8 Hz), 7.02 (d, 2H, J=8 Hz), 4.63 (m, 1H),3.81-3.85 (m, 1H), 3.67-3.76 (m, 2H), 3.43-3.47 (m, 1H), 2.40 (d, 2H,J=7.5 Hz), 1.97 (b, 2H), 1.88 (b, 2H), 1.18 (t, 3H, J=7.5 Hz).

Example 17.{4-[4-(2-Chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-cyclopropyl-methanone

Analysis: LCMS m/z=407 (M+1); ¹H NMR (CDCl₃) δ: 8.09 (s, 1H), 8.05 (d,1H, J=8 Hz), 7.82 (d, 1H, J=8 Hz), 7.74 (t, 1H, J=7.5 Hz), 7.58 (t, 1H,J=7.5 Hz), 7.47 (d, 2H, J=8 Hz), 7.02 (d, 2H, J=8 Hz), 4.64 (q, 1H, J=4Hz), 3.95 (b, 1H), 3.82 (b, 1H), 3.65-3.71 (m, 2H), 1.88-2.00 (b, 4H),1.76-1.82 (m, 1H), 0.99-1.02 (m, 2H), 0.76-0.79 (m, 2H).

Example 18.1-{4-[4-(2-Methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=391 (M+1); ¹H NMR (CDCl₃) δ: 7.95 (s, 1H), 7.86 (d,1H, J=8 Hz), 7.73 (d, 1H, J=8 Hz), 7.57-7.63 (m, 3H), 7.38 (t, 1H, J=7.5Hz), 7.00 (d, 2H, J=8 Hz), 4.61 (q, 1H, J=4 Hz), 4.10 (s, 3H), 3.78-3.83(m, 1H), 3.65-3.75 (m, 2H), 3.40-3.46 (m, 1H), 2.37 (q, 2H, J=7.5 Hz),1.95 (b, 2H), 1.87 (b, 2H), 1.17 (t, 3H, J=7.5 Hz).

Example 19.Cyclopropyl-{4-[4-(5,6,7,8-tetrahydro-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=377 (M+1); ¹H NMR (DMSO-d6-HCl salt) δ: 8.88 (s, 1H),8.47 (s, 1H), 7.78 (d, 2H, J=8 Hz), 7.16 (d, 1H, J=8 Hz), 4.76 (q, 1H,J=4 Hz), 3.97 (b, 1H), 3.87 (b, 1H), 3.29 (b, 2H), 3.02 (m, 2H), 2.93(m, 2H), 1.97-2.03 (m, 2H), 1.89 (m, 3H), 1.81 (m, 2H), 1.64 (b, 1H),1.53 (b, 1H), 0.70-0.74 (m, 4H).

Example 20.Cyclobutyl-{4-[4-(5,6,7,8-tetrahydroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=391 (M+1): ¹H NMR (DMSO-d6-HCl salt) δ: 8.89 (s, 1H),8.53 (s, 1H), 7.79 (d, 2H, J=8 Hz), 7.14 (d, 2H, J=8 Hz), 4.73 (m, 1H),3.84 (m, 1H), 3.36 (m, 2H), 3.26 (m, 2H), 3.05 (m, 2H), 2.94 (m, 2H),2.09-2.19 (m, 4H), 3.17-3.92 (m, 8H), 1.53 (m, 2H).

Example21.1-{4-[4-(5,6,7,8-Tetrahydroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=365 (M+1); ¹H NMR (DMSO-d6-HCl salt) δ: 8.90 (s, 1H),8.54 (s, 1H), 7.79 (d, 2H, J=8 Hz), 7.15 (d, 2H, J=8 Hz), 4.74 (m, 1H),3.87 (m, 1H), 3.68 (m, 1H), 3.24-3.37 (m, 2H), 3.05 (m, 2H), 2.94 (m,2H), 2.33 (q, 2H, J=7 Hz), 1.81-1.90 (m, 6H), 1.61 (m, 1H), 1.52 (m,1H), 0.98 (t, 3H, J=7 Hz).

Example 22.1-{4-[4-(8-Fluoroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=379 (M+1); ¹H NMR (DMSO-d6) δ: 8.97 (d, 1H, J=4 Hz),8.44 (d, 1H, J=8 Hz), 7.87 (d, 1H, J=8 Hz), 7.74 (t, 1H, J=7.5 Hz),7.61-7.66 (m, 3H), 7.15 (d, 2H, J=8 Hz), 4.72 (q, 1H, j=4 Hz), 3.89 (b,1H), 3.70 (b, 1H), 3.38 (m, 1H), 3.26 (m, 1H), 2.34 (q, 2H, J=7.5 Hz),1.98 (b, 2H), 1.63 (m, 1H), 1.54 (m, 1H), 1.00 (t, 3H, J=7.5 Hz).

Example 23.Cyclopropyl-{4-[4-(8-fluoroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=391 (M+1); ¹H NMR (DMSO-d6) δ: 8.97 (m, 1H), 8.44 (d,1H, J=8 Hz), 7.87 (d, 1H, J=8 Hz), 7.75 (t, 1H, J=7.5 Hz), 7.61-7.67 (m,3H), 7.16 (d, 2H, J=8 Hz), 4.75 (q, 1H, J=4 Hz), 4.00 (b, 1H), 3.91 (b,1H), 3.56 (b, 1H), 3.26-3.34 (m, 2H), 1.98-2.04 (m, 3H), 1.67 (b, 1H),1.56 (b, 1H), 0.70-0.74 (m, 4H).

Example 24.Cyclobutyl-{4-[4-(8-fluoroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=405 (M+1); ¹H NMR (DMSO-d6) δ: 8.97 (m, 1H), 8.44 (d,1H, J=8 Hz), 7.87 (d, 2H, J=8 Hz), 7.73 (m, 1H), 7.61-7.66 (m, 3H), 7.14(d, 2H, J=8 Hz), 4.70 (q, 1H, J=4 Hz), 3.85-3.90 (m, 1H), 3.57-3.60 (m,1H), 3.34-3.39 (m, 1H), 3.22-3.29 (m, 2H), 2.06-2.20 (m, 4H), 1.86-1.95(m, 3H), 1.72-1.77 (m, 1H), 1.52-1.60 (m, 2H).

Example25.1-{4-[4-(8-Fluoro-2-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=393 (M+1); ¹H NMR (DMSO-d6) δ: 8.57 (d, 1H, J=7 Hz),7.92 (d, 1H, J=8 Hz), 7.78 (m, 1H), 7.65-7.69 (m, 3H), 7.18 (d, 2H, J=8Hz), 4.8 (m, 1H), 3.95 (b, 1H), 3.70 (b, 1H), 3.33-3.39 (m, 1H),3.24-3.29 (m, 1H), 2.80 (s, 3H), 2.34 (q, 2H, J=7 Hz), 1.94 (b, 2H),1.63 (b, 1H), 1.53 (b, 1H), 1.00 (t, 3H, J=7 Hz).

Example 26.Cyclopropyl-{4-[4-(8-fluoro-2-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=405 (M+1); ¹H NMR (DMSO-d6) δ: 8.45 (d, 1H, J=7 Hz),7.87 (d, 1H, J=7 Hz), 7.72 (m, 1H), 7.65 (d, 1H, J=8 Hz), 7.60 (d, 1H,J=8.5 Hz), 7.16 (d, 2H, J=8 Hz), 4.74 (m, 1H), 4.00 (b, 1H), 3.90 (b,1H), 3.56 (b, 1H), 3.28 (b, 1H), 2.76 (s, 3H), 1.98-2.04 (m, 3H), 1.66(b, 1H), 1.56 (b, 1H), 0.70-0.74 (m, 4H).

Example 27.Cyclobutyl-{4-[4-(8-fluoro-2-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=419 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ: 8.36 (d, 1H,J=7 Hz), 7.82 (d, 1H, J=7 Hz), 7.62-7.68 (m, 3H), 7.53 (d, 1H, J=7.5Hz), 7.14 (d, 2H, J=8 Hz), 4.70 (m, 1H), 3.8 (b, 1H), 3.57 (m, 1H), 3.35(m, 1H), 3.22 (m, 2H), 2.72 (s, 3H), 2.09-2.20 (m, 4H), 1.86-1.95 (m,3H), 1.75 (m, 1H), 1.52-1.57 (m, 2H).

Example 28.{4-[4-(5-Fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=421 (M+1); ¹H NMR (DMSO-d6) δ: 9.19 (s, 1H), 8.72 (d,0.5H, J=5 Hz), 8.46 (d, 0.5H, J=2, 5 Hz), 8.28 (b, 1H), 7.64 (d, 2H, J=8Hz), 7.48-7.53 (m, 1H), 7.36-7.41 (m, 1H), 7.06 (d, 2H, J=8 Hz), 4.65(m, 2H), 3.84-3.98 (m, 3H), 2.31 (m, 1H), 1.89-2.10 (m, 8H), 1.44-1.55(m, 4H).

Example 29.1-{4-[4-(5-Fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=379 (M+1); ¹H NMR (DMSO-d6) δ: 9.28 (s, 1H), 8.66 (s,1H), 7.84 (m, 3H), 7.55-7.62 (m, 2H), 7.17 (d, 2H, J=8 Hz), 4.72 (m,1H), 3.88 (m, 1H), 3.70 (m, 1H), 3.28-3.38 (m, 2H), 2.34 (q, 2H, J=7Hz), 1.93-1.99 (m, 2H), 1.53-1.64 (m, 2H), 1.00 (t, 3H, J=7 Hz).

Example 30.Cyclopropyl-{4-[4-(5-fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=391 (M+1); ¹H NMR (DMSO HCl salt) δ: 9.29 (s, 1H),8.68 (s, 1H), 7.86 (m, 3H), 7.54-7.64 (m, 2H), 7.18 (d, 2H, J=8 Hz),4.75 (m, 1H), 3.99 (b, 1H), 3.90 (b, 1H), 3.56 (b, 1H), 3.29 (b, 1H),1.98-2.03 (m, 3H), 1.66 (b, 1H), 1.56 (b, 1H), 0.70-0.74 (m, 4H).

Example 31.Cyclobutyl-{4-[4-(5-fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=405 (M+1); ¹H NMR (DMSO-d6) δ: 9.28 (s, 1H), 8.66 (s,1H), 7.85 (m, 3H), 7.53-7.64 (m, 2H), 7.16 (d, 2H, J=8 Hz), 4.72 (q, 1H,J=4 Hz), 3.85-3.89 (m, 1H), 3.57-3.60 (m, 1H), 3.34-3.39 (m, 1H),3.23-3.29 (m, 2H), 2.05-2.20 (m, 4H), 1.86-1.95 (m, 3H), 1.72-1.77 (m,1H), 1.52-1.60 (m, 2H).

Example 32.1-{4-[4-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1.4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester

Triphenylphosphine (9.53 g, 36.4 mmol), and DEAD (40% w/w DEAD intoluene, 16.1 mL, 40.9 mmol) in THF (80 mL) was cooled at 0° C. andstirred under nitrogen atmosphere. A mixture of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5.0 g, 22.7 mmol)and 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (5.72 g, 28.4mmol) in THF (10 mL) was added dropwise to the reaction. The coolingbath was removed and furthered stirred at rt for 20 h. The reaction wasevaporated under vacuum, stirred with ether, and the white solidfiltered off. The filtrate was evaporated under vacuum and purified byISCO silica gel chromatography (0-20% EtOAc/hexanes) to obtain4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (6.3 g, 69%). LCMS m/z=404 (M+1).

Step 2.4-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester

Palladium acetate (0.0111 g, 0.0496 mmol) and triphenylphosphine (0.0520g, 0.198 mmol) were stirred 15 min under an atmosphere of nitrogen.4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (0.40 g, 0.99 mmol),5-bromo-1H-pyrrolo[2,3-b]pyridine (0.235 g, 1.19 mmol), DMF (4 mL) and 1M Na₂CO₃ (4 mL) were added and heated at 80° C. for 18 h. The mixturewas concentrated, dissolved in EtOAc, washed with 1N Na₂CO₃, water andbrine, then dried (MgSO₄). The product was purified by ISCO (silica get,80 g column; 40-80% EtOAc/hexanes) to give a white solid (0.25 g, 64%).Analysis: LCMS m/z=394 (M+1): ¹H NMR (CDCl₃) δ 9.16 (br. s., 1H), 8.51(d, J=2.0 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H), 7.47-7.61 (m, 2H), 7.30-7.38(m, 1H), 6.99-7.10 (m, 2H), 6.55 (dd, J=3.4, 1.9 Hz, 1H), 4.52 (dt,J=7.1, 3.6 Hz, 1H), 3.69-3.80 (m, 2H), 3.31-3.46 (m, 2H), 1.93-2.00 (m,2H), 1.76-1.84 (m, 2H), 1.48 (s, 9H).

Step 3. 5-[4-(Piperidin-4-yloxy)-phenyl]-1H-pyrrolo[2,3-b]pyridine

4-[4-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (200 mg, 0.51 mmol) was added 6M HCl in dioxane (4mL, 20 mmol) and stirred at rt for 6 h. The mixture was concentrated,and triturated with ether to give a light yellow solid (150 mg, 98%).Analysis: LCMS m/z=294 (M+1); ¹H NMR (DMSO-d₆) δ 12.25 (br. s., 1H),9.19 (br. s., 2H), 8.43-8.65 (m, 2H), 7.59-7.73 (m, 3H), 7.15 (d, J=8.5Hz, 2H), 6.64 (d, J=1.3 Hz, 1H), 4.74 (br. s., 1H), 3.23 (br. s., 2H),3.09 (d, J=4.3 Hz, 2H), 2.14 (d, J=3.5 Hz, 2H), 1.90 (d, J=9.3 Hz, 2H)

Step 4.1-{4-[4-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

5-[4-(Piperidin-4-yloxy)phenyl]-1H-pyrrolo[2,3-b]pyridine (0.043 g, 0.15mmol) and DIPEA (0.0771 mL, 0.443 mmol) in DCM (2 mL) was addedpropanoyl chloride (0.026 mL, 0.295 mmol). After 2 h stirring at rt themixture was concentrated, dissolved in EtOAc and washed with 1N Na₂CO₃and brine, then dried over MgSO₄. The product was purified by ISCO (4 gsilica gel column, 0-5% MeOH/DCM) to give an oil. The HCl saltsynthesized from by adding 1N HCl ether to a dCM solution of base give awhite solid (32 mg, 62%). Analysis: LCMS m/z=350 (M+1): ¹H NMR (DMSO,HCl salt) δ: 11.89 (s, 1H), 8.51 (s, 1H), 8.29 (s, 1H), 7.63 (d, 2H, J=8Hz), 7.54 (m, 1H), 7.09 (d, 2H, J=8 Hz), 6.55 (s, 1H), 4.67 (m, 1H),3.87 (b, 1H), 3.69 (b, 1H), 3.34 (m, 1H), 3.26 (m, 1H), 2.33 (q, 2H, J=7Hz), 1.91-1.97 (b, 2H), 1.61 (m, 1H), 1.51 (m, 1H), 0.99 (t, 3H J=7 Hz).

The following examples were synthesized from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester using the general procedure.

Example 33.Cyclopropyl-{4-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=362 (M+1); ¹H NMR (DMSO-d₆ HCl salt) δ: 11.92 (s,1H), 8.51 (s, 1H), 8.30 (s, 1H), 7.65 (d, 2H, J=8 Hz), 7.56 (m, 1H),7.10 (d, 2H, J=8 Hz), 6.55 (m, 1H), 4.70 (m, 1H), 3.98 (b, 1H), 3.89 (b,1H), 3.56 (b, 1H), 3.28 (b, 1H), 1.93-2.03 (m, 3H), 1.64 (b, 1H), 1.54(b, 1H), 0.69-0.74 (m, 4H).

Example 34.Cyclopropyl-{4-[4-(7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=403 (M+1): ¹H NMR (CDCl₃) δ: 9.07 (s, 1H), 8.18 (s,1H), 7.73 (s, 1H, J=8 Hz), 7.62 (d, 2H, J=8 Hz), 7.44 (s, 1H), 7.22 (dd,1H, J=2, 8 Hz), 7.05 (d, 2H, J=8 Hz), 4.64 (m, 1H), 3.97 (s, 3H), 3.83(b, 2H), 3.64-3.70 (m, 2H), 1.87-2.00 (b, 4H), 1.75-1.81 (m, 1H), 1.00(m, 2H), 0.77-0.79 (m, 2H).

Example 35.1-{4-[4-(7-Methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=391 (M+1); ¹H NMR (CDCl₃) δ: 9.06 (d, 1H, J=2 Hz),8.17 (d, 1H, J=2 Hz), 7.73 (d, 1H, J=9 Hz), 7.61 (d, 2H, J=8 Hz), 7.44(d, 1H, J=2 Hz), 7.22 (dd, 1H, J=2, 8 Hz), 7.04 (d, 2H, J=8 Hz), 4.62(q, 1H, J=4 Hz), 3.97 (s, 3H), 3.80-3.84 (m, 1H), 3.67-3.75 (m, 2H),3.42-3.48 (m, 1H), 2.38 (q, 2H, J=7.5 Hz), 1.96 (b, 2H), 1.87 (b, 2H),1.17 (t, 3H, J=7.5 Hz).

Example 36.1-{4-[4-(8-Methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=375 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ: 9.13 (m, 1H),8.83 (s, 1H), 8.07 (d, 1H, J=8 Hz), 7.86 (m, 1H), 7.67 (d, 1H, J=8 Hz),7.40 (d, 2H, J=8 Hz), 7.13 (d, 2H, J=8 Hz), 4.70 (q, 1H, J=4 Hz),3.90-393 (m, 1H), 3.71-3.74 (m, 1H), 3.33-3.39 (m, 1H), 3.24-3.28 (m,1H), 2.72 (s, 3H), 2.34 (q, 2H, J=7 Hz), 1.95 (b, 2H), 1.64 (b, 1H),1.53 (b, 1H), 1.00 (t, 3H, J=7 Hz).

Example 37.Cyclopropyl-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=387 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ: 9.06 (s, 1H),8.63 (s, 1H), 7.97 (m, 1H), 7.72 (m, 1H), 7.59 (m, 1H), 7.40 (d, 2H, J=7Hz), 7.14 (d, 2H, J=7 Hz), 4.73 (m, 1H), 4.12 (b, 1H), 3.91 (b, 1H),3.71 (b, 1H), 3.28 (b, 1H), 2.70 (s, 3H), 1.98-2.04 (m, 3H), 1.67 (b,1H), 1.56 (b, 1H), 0.70-0.74 (m, 4H).

Example 38.Cyclobutyl-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=401 (M+1); ¹H NMR (DMSO-d6 HCL salt) δ: 9.08 (m, 1H),8.73 (s, 1H), 8.01 (d, 1H, J=8 Hz), 7.79 (s, 1H), 7.62 (d, 1H, J=8 Hz),7.39 (d, 2H, J=7 Hz), 7.12 (d, 2H, J=7 Hz), 4.68 (m, 1H), 3.88-3.91 (m,1H), 3.58-3.61 (m, 1H), 3.35-3.39 (m, 1H), 3.23-3.28 (m, 2H), 2.70 (s,3H), 2.08-2.23 (m, 4H), 1.86-1.95 (m, 3H), 1.72-1.77 (m, 1H), 1.53-1.59(m, 2H).

Example 39.Cyclopropyl-[4-(4-quinolin-2-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS m/z=373 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ: 8.66 (s, 1H),8.18-8.26 (m, 4H), 8.08 (d, 1H, J=8 Hz), 7.88 (t, 1H, J=7 Hz), 7.68 (t,1H, J=7 Hz), 7.22 (d, 2H, J=7 Hz), 4.81 (q, 1H, J=4 Hz), 4.01 (b, 1H),3.90 (b, 1H), 3.58 (b, 1H), 3.30 (b, 1H), 1.98-2.04 (m, 3H), 1.66 (b,1H), 1.57 (b, 1H), 0.70-0.74 (m, 4H).

Example 40. 1-[4-(4-Quinolin-2-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=361 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ: 8.74 (s, 1H),8.25 (m, 4H), 8.14 (d, 1H, J=8 Hz), 7.93 (m, 1H), 7.72 (m, 1H), 7.23 (d,2H, J=8 Hz), 4.80 (m, 1H), 3.90 (m, 1H), 3.74 (m, 1H), 3.34-3.39 (m,1H), 3.25-3.30 (m, 1H), 2.34 (q, 2H, J=7 Hz), 1.95-2.01 (b, 2H), 1.65(b, 1H), 1.54 (b, 1H), 1.00 (t, 3H, J=7 Hz).

Example 41.Cyclobutyl-[4-(4-quinolin-2-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS m/z=387 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ: 8.73 (s, 1H),8.26 (m, 4H), 8.12 (d, 1H, J=8 Hz), 7.92 (m, 1H), 7.72 (m, 1H), 7.22 (d,2H, J=8 Hz), 4.79 (m, 1H), 3.87-3.90 (m, 1H), 3.57-3.61 (m, 1H),3.35-3.39 (m, 1H), 3.23-3.30 (m, 2H), 2.05-2.22 (m, 4H), 1.86-1.96 (m,3H), 1.70-1.78 (m, 1H), 1.50-1.63 (m, 2H).

Example 42.[4-(4-Quinolin-2-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=403 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ: 8.65 (s, 1H),8.17-8.25 (m, 4H), 8.08 (d, 1H, J=8 Hz), 7.89 (m, 1H), 7.68 (m, 1H),7.21 (d, 2H, J=8 Hz), 4.80 (m, 1H), 4.69 (m, 1H), 3.71-3.92 (m, 3H),3.23-3.49 (m, 2H), 1.98-2.08 (m, 3H), 1.79-1.89 (m, 2H), 1.53-1.67 (m,2H), 1.24-1.28 (m, 2H).

Example 43.1-[4-(4-Isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=361 (M+1); ¹H NMR (DMSO-d6) δ: 9.36 (s, 1H), 8.32 (s,1H), 8.15 (d, 2H, J=8 Hz), 8.10 (d, 1H, J=7.5 Hz), 7.98 (d, 1H, J=7.5Hz), 7.77 (m, 1H), 7.63 (m, 1H), 7.11 (d, 2H, J=8 Hz), 4.71 (q, 1H, J=4Hz), 3.24-3.35 (m, 3H), 3.19 (b, 1H), 3.70 (b, 1H), 2.34 (q, 2H, J=7Hz), 1.93-1.98 (b, 2H), 1.63 (b, 1H), 1.53 (b, 1H), 1.00 (t, 3H, J=7Hz).

Example 44.Cyclopropyl-[4-(4-isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS m/z=373 (M+1); ¹H NMR (DMSO-d6) δ: 9.36 (s, 1H), 8.32 (s,1H), 8.16 (d, 2H, J=8.8 Hz), 8.10 (d, 1H, J=8 Hz), 7.98 (d, 1H, J=8 Hz),7.77 (m, 1H), 7.63 (m, 1H), 7.12 (d, 2H, J=8.8 Hz), 4.74 (q, 1H, J=4Hz), 3.99 (b, 1H), 3.90 (b, 1H), 3.56 (b, 1H), 3.29 (m, 1H), 1.92-2.10(m, 3H), 1.66 (b, 1H), 1.55 (b, 1H), 0.69-0.75 (m, 4H).

Example 45.Cyclobutyl-[4-(4-isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS m/z=387 (M+1); ¹H NMR (DMSO-d6) δ: 9.36 (s, 1H), 8.32 (s,1H), 8.15 (d, 2H, J=9 Hz), 8.09 (d, 1H, J=8 Hz), 7.98 (d, 1H, J=8 Hz),7.77 (m, 1H), 7.63 (m, 1H), 7.14 (d, 2H, J=9 Hz), 4.70 (m, 1H),3.86-3.89 (m, 1H), 3.56-3.60 (m, 1H), 3.23-3.38 (m, 3H), 2.07-2.22 (m,4H), 1.85-1.94 (m, 3H), 1.70-1.77 (m, 1H), 1.52-1.56 (m, 2H).

Example 46.[4-(4-Isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=403 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ: 9.51 (s, 1H),8.47 (s, 1H), 8.23 (d, 1H, J=8 Hz), 8.12 (d, 2H, J=9 Hz), 8.08 (d, 1H,J=8 Hz), 7.89 (m, 1H), 7.73 (m, 1H), 7.16 (d, 2H, J=9 Hz), 4.75 (m, 1H),4.70 (m, 1H), 3.70-3.90 (m, 2H), 3.57-3.64 (m, 1H), 3.10-3.16 (m, 1H),1.94-2.08 (m, 2H), 1.77-1.89 (m, 2H), 1.52-1.66 (b, 2H), 1.23-1.28 (m,4H).

Example 47.1-{4-[4-(4-Chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=395 (M+1); ¹H NMR (DMSO HCl) δ: 8.91 (s, 1H), 8.32(d, 1H, J=8 Hz), 8.14 (d, 1H, J=8 Hz), 7.89-7.93 (m, 1H), 7.81-7.88 (m,1H), 7.56 (d, 2H, J=8 Hz), 7.16 (d, 2H, J=8 Hz), 4.73 (q, 1H, J=4 Hz),3.91 (b, 1H), 3.71 (b, 1H), 3.33-3.39 (m, 1H), 3.24-3.28 (m, 1H), 2.34(q, 2H, J=7 Hz), 1.94-2.00 (b, 2H), 1.63 (b, 1H), 1.55 (b, 1H), 1.00 (t,3H, J=7 Hz).

Example 48.{4-[4-(4-Chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-cyclopropyl-methanone

Analysis: LCMS m/z=407 (M+1); ¹H NMR (DMSO HCl) δ: 8.90 (s, 1H), 8.32(d, 1H, J=8 Hz), 8.13 (m, 1H), 7.90 (t, 1H, J=8 Hz), 7.83 (m, 1H), 7.56(d, 2H, J=8 Hz), 7.17 (d, 2H, J=8 Hz), 4.75 (q, 1H, J=4 Hz), 3.93 (b,2H), 3.56 (b, 1H), 3.28 (b, 1H), 1.96-2.04 (m, 3H), 1.67 (b, 1H), 1.56(b, 1H), 0.70-0.74 (m, 4H).

Example 49.{4-[4-(4-Chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-cyclobutyl-methanone

Analysis: LCMS m/z=421 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ: 8.92 (s, 1H),8.32 (d, 1H, J=8 Hz), 8.14 (d, 1H), 7.91 (m, 1H), 7.84 (m, 1H), 7.56 (d,2H, J=8 Hz), 7.15 (d, 2H, J=8 Hz), 4.72 (m, 1H), 3.89 (b, 1H), 3.60 (b,1H), 3.33-3.39 (m, 1H), 3.22-3.29 (m, 2H), 2.08-2.20 (m, 4H), 1.86-1.96(m, 3H), 1.72-1.77 (m, 1H), 1.53-1.60 (m, 2H).

Example 50.1-{4-[4-(4-Methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=391 (M+1); ¹H NMR (CDCl₃) δ: 8.84 (s, 1H), 8.20 (d,1H, J=8 Hz), 8.03 (d, 1H, J=8 Hz), 7.78 (t, 1H, J=8.5 Hz), 7.60-7.68 (m,3H), 7.14 (d, 2H, J=8 Hz), 4.70 (q, 1H, J=4 Hz), 3.90 (b, 1H), 3.70 (b,1H), 3.68 (s, 3H), 3.43-3.48 (m, 2H), 2.34 (q, 2H, J=7 Hz), 1.97 (b,2H), 1.65 (b, 1H), 155 (b, 1H), 1.00 (t, 3H, J=7 Hz).

Example 51.1-[4-(4-Furo[3,2-b]pyridin-6-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=351 (M+1); 1H NMR (DMSO-d6) δ: 8.81 (d, 1H, J=2 Hz),8.31 (d, 1H, J=2.3 Hz), 8.27 (m, 1H), 7.71 (d, 2H, J=8 Hz), 7.15 (m,1H), 7.13 (d, 2H, J=8 Hz), 4.70 (q, 1H, J=4 Hz), 3.88 (m, 1H), 3.70 (m,1H), 3.37 (m, 1H), 3.26 (m, 1H), 2.33 (q, 2H, J=7 Hz), 1.97 (b, 2H),1.62 (m, 1H), 1.52 (m, 1H), 0.99 (t, 3H, J=7 Hz).

Example 52.Cyclopropyl-[4-(4-furo[3,2-b]pyridin-6-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS m/z=363 (M+1); ¹H NMR (DMSO-d6) δ: 8.82 (s, 1H), 8.31 (d,1H, J=2 Hz), 8.27 (s, 1H), 7.72 (d, 2H, J=8 Hz), 7.15 (s, 1H), 7.12 (d,2H, J=8 Hz), 4.72 (q, 1H, J=4 Hz), 3.98 (b, 1H), 3.88 (b, 1H), 3.55 (b,1H), 3.28 (m, 1H), 1.93-2.01 (m, 3H), 1.64 (b, 1H), 1.51 (b, 1H),0.69-0.73 (m, 4H).

Example 53.1-{4-[4-(6-Methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=391 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ: 9.36 (s, 1H),9.08 (s, 1H), 8.22 (d, 1H, J=9 Hz), 7.89 (d, 2H, J=8 Hz), 7.66 (m, 2H),7.20 (d, 2H, J=8 Hz), 4.76 (q, 1H, J=4 Hz), 3.97 (s, 3H), 3.89 (m, 1H),3.71 (m, 1H), 3.34-3.39 (m, 1H), 3.25-3.30 (m, 1H), 2.34 (q, 2H, J=7Hz), 1.97 (b, 2H), 1.64 (m, 1H), 1.54 (m, 1H), 1.00 (t, 3H, J=7 Hz).

Example 54.Cyclopropyl-{4-[4-(6-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=403 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ: 9.23 (s, 1H),9.04 (s, 1H), 8.19 (d, 1H, J=9 Hz), 7.89 (d, 2H, J=8 Hz), 7.46 (m, 2H),7.21 (d, 2H, J=8 Hz), 4.78 (q, 1H, J=4 Hz), 4.05 (b, 1H), 3.97 (s, 3H),3.91 (b, 1H), 3.57 (b, 1H), 3.29 (b, 1H), 1.96-2.04 (m, 3H), 1.65 (b,1H), 1.56 (b, 1H), 0.69-0.75 (m, 4H).

Example 55.1-{4-[4-(6,7-Dimethoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=421 (M+1); ¹H NMR (DMSO HCl salt) δ: 9.30 (s, 1H),9.10 (s, 1H), 7.86 (d, 2H, J=8 Hz), 7.66 (d, 2H, J=7 Hz), 7.20 (d, 2H,J=8 Hz), 4.75 (q, 1H, J=4 Hz), 4.03 (s, 3H), 3.99 (s, 3H), 3.89 (m, 1H),3.71 (m, 1H), 3.37 (m, 1H), 3.27 (m, 1H), 2.34 (q, 2H, J=7 Hz), 1.99 (b,2H), 1.63 (m, 1H), 1.53 (m, 1H), 1.00 (t, 3H, J=7 Hz).

Example 56.Cyclopropyl-{4-[4-(6,7-dimethoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=433 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ: 9.26 (s, 1H),9.01 (s, 1H), 7.86 (d, 2H, J=8 Hz), 7.64 (s, 1H), 7.56 (s, 1H), 7.20 (d,2H, J=8 Hz), 4.77 (q, 1H, J=4 Hz), 4.02 (s, 3H), 3.98 (s, 3H), 3.90 (b,1H), 2.57 (b, 2H), 3.29 (m, 1H), 1.96-2.03 (m, 3H), 1.66 (b, 1H), 1.53(br, 1H), 0.70-0.75 (m, 4H).

Example 57.1-{4-[4-(8-Methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=391 (M+1); ¹H NMR (DMSO-d6 base) δ: 9.14 (d, 1H, J=2Hz), 8.51 (d, 1H, J=2 Hz), 7.08 (d, 2H, J=8 Hz), 7.54 (m, 2H), 7.16 (m,3H), 4.72 (q, 1H, J=4 Hz), 3.98 (s, 3H), 3.99 (m, 1H), 3.70 (m, 1H),3.38 (m, 1H), 3.25 (m, 1H), 2.34 (q, 2H, J=7 Hz), 1.98 (b, 2H), 1.62 (b,1H), 1.53 (b, 1H), 1.00 (t, 3H, J=7 Hz).

Example 58.Cyclopropyl-{4-[4-(8-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=403 (M+1); ¹H NMR (DMSO-d6 base) δ: 9.14 (d, 1H, J=2Hz), 8.51 (d, 1H, J=2 Hz), 7.81 (d, 2H, J=8 Hz), 7.54 (m, 2H), 7.16 (m,3H), 4.74 (q, 1H, J=4 Hz), 4.02 (b, 1H), 3.98 (s, 3H), 3.89 (b, 1H),3.57 (b, 1H), 3.29 (m, 1H), 1.94-2.04 (m, 3H), 1.66 (b, 1H), 1.55 (b,1H), 0.69-0.74 (m, 4H).

Example 59.{4-[4-(8-Chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-cyclopropyl-methanone

Analysis: LCMS m/z=407 (M+1); ¹H NMR (DMSO-d₆) δ: 9.05 (d, 1H, J=4 Hz),8.48 (d, 1H, J=8 Hz), 8.01 (d, 1H, J=8 Hz), 7.62-7.68 (m, 2H), 7.50 (d,2H, J=8 Hz), 7.1 (d, 2H, J=8 Hz), 4.73 (q, 1H, J=4 Hz), 4.01 (b, 1H),3.92 (b, 1H), 3.56 (b, 1H), 3.22 (b, 1H), 1.98-2.04 (m, 3H), 1.68 (b,1H), 1.56 (b, 1H), 0.70-0.74 (m, 4H).

Example 60.1-{4-[4-(4-Methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=375 (M+1); ¹H NMR (DMSO-d₆) δ: 9.13 (s, 1H), 8.47 (d,1H, J=8.5 Hz), 8.33 (d, 1H, J=9 Hz), 8.09 (t, 1H, J=7.5 Hz), 7.95 (t,1H, J=7.5 Hz), 7.49 (d, 2H, J=8 Hz), 7.20 (d, 2H, J=8 Hz), 4.74 (q, 1H,J=4 Hz), 3.91 (b, 1H), 3.71 (b, 1H), 3.34-3.39 (m, 1H), 3.24-3.29 (m,1H), 2.83 (s, 3H), 2.34 (q, 2H, J=7 Hz), 1.94 (b, 2H), 1.65 (b, 1H),1.55 (b, 1H), 1.00 (t, 3H, J=7 Hz).

Example 61.Cyclopropyl-{4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=387 (M+1); ¹H NMR (DMSO-d₆ HCl salt) δ: 1H NMR 9.06(s, 1H), 8.42 (d, J=8.3 Hz, 1H), 8.24 (d, J=8.3 Hz, 1H), 8.02 (t, J=7.7Hz, 1H), 7.83-7.96 (m, 1H), 7.41-7.58 (m, 2H), 7.20 (d, J=8.5 Hz, 2H),4.76 (dt, J=7.8, 3.9 Hz, 1H), 4.01-4.09 (m, 1H), 3.89-3.96 (m, 1H), 3.58(br. s., 1H), 3.25-3.33 (m, 1H), 1.94-2.13 (m, 3H), 1.68 (br. s., 1H),1.57 (br. s., 1H), 0.67-0.81 (m, 4H).

Example 62.Cyclobutyl-{4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=401 (M+1); ¹H NMR (DMSO-d₆ HCl salt) δ: 9.09 (s, 1H),8.45 (d, J=8.5 Hz, 1H), 8.31 (d, J=8.3 Hz, 1H), 7.86-8.13 (m, 2H), 7.49(d, J=8.5 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 4.61-4.81 (m, 1H), 3.84-3.97(m, 1H), 3.60 (d, J=13.8 Hz, 1H), 3.32-3.43 (m, 1H), 3.18-3.32 (m, 2H),2.81 (s, 3H), 2.04-2.23 (m, 4H), 1.92 (dd, J=19.4, 8.9 Hz, 4H),1.70-1.82 (m, 1H), 1.50-1.68 (m, 3H).

Example 63.1-{4-[4-(7-Methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=375 (M+1): ¹H NMR (DMSO-d₆) δ: 9.29 (d, J=2.3 Hz,1H), 8.79 (br. s., 1H), 7.95 (d, J=8.0 Hz, 1H), 7.87 (d, J=8.8 Hz, 2H),7.69 (d, J=7.0 Hz, 1H), 7.56-7.65 (m, 1H), 7.19 (d, J=8.8 Hz, 2H), 4.74(dt, J=7.7, 4.0 Hz, 1H), 3.83-4.00 (m, 1H), 3.64-3.80 (m, 1H), 3.19-3.52(m, 2H), 2.78 (s, 3H), 2.31-2.42 (m, 2H), 2.35 (q, J=7.5 Hz, 2H),1.86-2.10 (m, 2H), 1.64 (d, J=8.5 Hz, 1H), 1.54 (d, J=8.3 Hz, 1H), 1.00(t, J=7.4 Hz, 3H).

Example 64.Cyclopropyl-{4-[4-(7-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=387 (M+1); ¹H NMR (DMSO-d₆) δ: 9.27 (d, J=2.3 Hz,1H), 8.67 (br. s., 1H), 7.81-8.01 (m, 3H), 7.65 (d, J=6.8 Hz, 1H),7.49-7.61 (m, 1H), 7.19 (d, J=8.5 Hz, 2H), 4.76 (br. s., 1H), 4.01 (br.s., 1H), 3.90 (br. s., 1H), 3.57 (br. s., 1H), 3.30 (br. s., 1H),2.73-2.82 (m, 3H), 2.01 (d, J=5.3 Hz, 3H), 1.68 (br. s., 1H), 1.57 (br.s., 1H), 0.48-0.81 (m, 4H).

Example 65.{4-[4-(4-Methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone

Analysis: LCMS m/z=417 (M+1): ¹H NMR (DMSO-d₆) δ: 9.13 (1H, s), 8.47(1H, d, J=8.3 Hz), 8.32 (1H, d, J=8.3 Hz), 8.08 (1H, t, J=7.7 Hz),7.90-8.00 (1H, m), 7.50 (2H, d, J=8.8 Hz), 7.20 (2H, d, J=8.5 Hz), 4.76(1H, d, J=3.5 Hz), 4.70 (1H, t, J=6.1 Hz), 3.69-4.00 (4H, m), 3.20-3.52(2H, m), 2.82 (3H, s), 1.93-2.12 (4H, m), 1.78-1.91 (2H, m), 1.49-1.73(2H, m).

Example 66.1-[4-(4-Quinoxalin-2-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=362 (M+1); ¹H NMR (DMSO-d₆ HCl salt) δ: 9.55 (s, 1H),8.31 (d, 1H, J=8 Hz), 8.08 (d, 1H, J=8 Hz), 7.79-7.87 (m, 2H), 7.19 (d,2H, J=8 Hz), 4.79 (m, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.37 (m, 1H),3.25 (m, 1H), 2.34 (q, 2H, J=7 Hz), 1.99 (b, 2H), 1.63 (b, 1H), 1.53 (b,1H), 1.00 (t, 3H, J=7 Hz).

Example 67.Cyclopropyl-[4-(4-quinoxalin-2-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS m/z=374 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ:9.55 (s, 1H),8.31 (d, 2H, J=9 Hz), 8.08-8.11 (m, 2H), 7.79-7.88 (m, 2H), 7.20 (d, 2H,J=8 Hz), 4.80 (q, 1H, J=4 Hz), 3.99 (b, 1H), 3.91 (b, 1H), 3.56 (b, 1H),3.28 (b, 1H), 1.98-2.08 (m, 3H), 1.67 (b, 1H), 1.57 (b, 1H), 0.70-0.74(m, 4H).

Example 68.[4-(4-Quinoxalin-2-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=404 (M+1); ¹H NMR (DMSO-d₆ HCl salt) δ: 9.55 (s, 1H),8.30 (d, 2H, J=8 Hz), 8.08-8.11 (m, 2H), 7.80-7.88 (m, 2H), 7.20 (d, 2H,J=8 Hz), 4.79 (m, 1H), 4.69 (m, 1H), 3.71-3.81 (m, 4H), 3.26-3.46 (m,2H), 1.95-2.01 (m, 4H), 1.78-1.89 (m, 2H), 1.54-1.68 (m, 2H).

Example 69.{4-[4-(8-Methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone

Analysis: LCMS m/z=417 (M+1); ¹H NMR (DMSO-d₆) δ 9.05-9.21 (m, 1H), 8.75(br. s., 1H), 8.05 (d, J=8.5 Hz, 1H), 7.76-7.89 (m, 1H), 7.66 (d, J=8.3Hz, 1H), 7.35-7.49 (m, 2H), 7.14 (d, J=8.5 Hz, 2H), 4.65-4.81 (m, 3H),3.70-3.98 (m, 5H), 3.15-3.50 (m, 3H), 2.71 (s, 3H), 1.91-2.19 (m, 4H),1.75-1.91 (m, 2H), 1.45-1.73 (m, 2H).

Example 70.{4-[4-(8-Methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(S)-tetrahydro-furan-2-yl-methanone

Analysis: LCMS m/z=417 (M+1); ¹H NMR (DMSO-d₆) δ: 8.97 (d, J=2.5 Hz,1H), 8.37 (d, J=8.0 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.55 (dd, J=8.3,4.3 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.38 (d, J=8.3 Hz, 2H), 7.11 (d,J=8.5 Hz, 2H), 4.70 (d, J=5.3 Hz, 2H), 3.69-4.03 (m, 4H), 3.38-3.58 (m,1H), 3.25 (br. s., 1H), 2.68 (s, 3H), 1.91-2.13 (m, 4H), 1.85 (dt,J=13.9, 6.7 Hz, 2H), 1.53-1.73 (m, 2H)

Example 71.{4-[4-(4-Chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone

Analysis: LCMS m/z=437 (M+1); ¹H NMR (DMSO-d₆) δ: 8.88 (s, 1H), 8.31 (d,1H, J=8 Hz), 8.12 (d, 1H, J=8 Hz), 7.89 (t, 1H, J=7 Hz), 7.82 (t, 1H,J=7 Hz), 7.55 (d, 2H, J=8 Hz), 7.16 (d, 2H, J=8 Hz), 4.68-4.74 (m, 2H),3.72-3.93 (m, 4H), 3.39-3.48 (m, 1H), 3.23-3.28 (m, 1H), 1.96-2.08 (m,4H), 1.80-1.87 (m, 2H), 1.66 (b, 1H), 1.56 (b, 1H).

Example 72.1-{4-[4-(4-Methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propane-1,2-dione

Analysis: LCMS m/z=389 (M+1); ¹H NMR (DMSO-d₆ HCl salt) δ: 9.09 (1H, s),8.45 (1H, d, J=8.5 Hz), 8.29 (1H, d, J=8.5 Hz), 8.05 (1H, t, J=7.7 Hz),7.86-7.98 (1H, m), 7.50 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz),4.73-4.87 (1H, m), 3.77-3.90 (2H, m), 3.53-3.65 (2H, m), 3.29-3.47 (3H,m), 2.40 (3H, s), 1.95-2.10 (2H, m), 1.55-1.78 (2H, m).

Example 73.Isoxazolidin-2-yl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone

Method A: 3-[4-(Piperidin-4-yloxy)-phenyl]-quinoline.2 HCl (0.180 g,0.477 mmol) in DCM (3 mL) was added triphosgene (0.0708 g, 0.238 mmol)on an ice bath. The mixture was warmed to rt, stirred 4 h, and then wasconcentrated. This material in DCM (4 mL) was added DIPEA (0.166 mL,0.954 mmol) and isoxazolidine.HCl (0.0627 g, 0.572 mmol) and stirred atrt for 2 h. The reaction was concentrated, dissolved in EtOAc and washedwith 1N Na₂CO₃ and brine and then dried (MgSO₄). The product waschromatographed on Isco (12 g silica gel, 0-5% MeOH/DCM) to give an oil.The HCl salt was prepared by adding 0.5 mL 1N HCl-ether to a DCMsolution of base, was recrystallized from DCM-ether and dried to give ayellow solid (140 mg, 72%). Analysis: LCMS m/z=404 (M+1); ¹H NMR(DMSO-d6 HCl salt) δ: 9.48 (s, 1H), 9.09 (s, 1H), 8.23 (d, 2H, J=7 Hz),7.90-7.97 (m, 3H), 7.82 (t, 1H, J=7.8 Hz), 7.20 (d, 2H, J=8 Hz), 4.75(q, 1H, J=4 Hz), 3.76-3.83 (m, 4H), 3.43 (t, 2H, J=7.5 Hz), 3.30-3.37(m, 2H), 2.13 (q, 2H, J=7 Hz), 1.98-2.02 (m, 2H), 1.58-1.66 (m, 2H).

The following examples were synthesized using the previous procedure.

Example 74.[4-(4-Isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-isoxazolidin-2-yl-methanone

Analysis: LCMS m/z=404 (M+1); ¹H NMR (DMSO-d₆ HCl salt) δ: 9.61 (s, 1H),8.56 (s, 1H), 8.31 (d, 1H, J=8.5 Hz), 8.11 (m, 3H), 7.97 (7, 1H, J=7Hz), 7.79 (t, 1H, J=7 Hz), 7.20 (d, 2H, J=8 Hz), 4.75 (q, 1H, J=4 Hz),3.81 (m, 4H), 4.43 (t, 2H, J=7 Hz), 3.31-3.36 (m, 2H), 2.13 (q, 2H, J=7Hz), 2.00 (b, 2H), 1.61-1.65 (m, 2H).

Example 75.Isoxazolidin-2-yl-{4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=418 (M+1); 1H NMR (DMSO-d₆ HCl salt) δ: 8.98 (s, 1H),8.35 (d, 1H, J=7.7 Hz), 7.84 (d, 1H, J=8 Hz), 7.53-7.56 (m, 1H), 7.46(d, 1H, J=8.5 Hz), 7.36 (d, 2H, J=8 Hz), 7.09 (d, 2H, J=8 Hz), 4.68 (b,1H), 3.81 (m, 4H), 3.43 (t, 2H, J=7 Hz), 3.3 (m, 2H), 2.67 (s, 3H),2.09-2.17 (m, 2H), 1.99 (b, 2H), 1.58-1.70 (m, 2H).

Example 76.{4-[4-(4-Chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-isoxazolidin-2-yl-methanone

Analysis: LCMS m/z=438 (M+1); 1H NMR (DMSO-d₆ HCl salt) δ: 9.13 (d, 1H,J=4 Hz), 8.85 (d, 1H, J=7 Hz), 8.08 (d, 1H, J=8 Hz), 7.85-7.89 (m, 1H),7.68 (d, 1H, J=8 Hz), 7.42 (d, 2H, J=8 Hz), 7.16 (d, 2H, J=8 Hz),4.69-4.73 (m, 2H), 3.78-3.83 (m, 4H), 3.43 (t, 2H, J=7 Hz), 3.29-3.36(m, 2H), 2.13 (q, 2H, J=7.2 Hz), 1.98-2.03 (m, 2H), 1.58-1.66 (m, 2H),

Example 77.{4-[4-(8-Chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-isoxazolidin-2-yl-methanone

Analysis: LCMS m/z=438 (M+1); ¹H NMR (DMSO-d6) δ: 9.05 (d, 1H, J=5 Hz),8.48 (d, 1H, J=8 Hz), 8.01 (d, 1H, J=8.5 Hz), 7.64-7.67 (m, 1H), 7.61(d, 1H, J=8 Hz), 7.49 (d, 2H, J=8 Hz), 7.12 (d, 2H, J=8 Hz), 4.70 (q,1H, J=4 Hz), 3.78-3.83 (m, 4H), 3.43 (t, 2H, J=7.5 Hz), 3.30-3.35 (m,2H), 2.13 (q, 2H, J=7.3 Hz), 1.98.2.03 (m, 2H), 1.58-1.66 (m, 2H).

Example 78.Isoxazolidin-2-yl-{4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=418 (M+1); ¹H NMR (DMSO-d₆) δ: 8.74 (s, 1H), 8.20 (d,1H, J=8 Hz), 8.03 (d, 1H, J=8 Hz), 7.78 (t, 1H, J=7.2 Hz), 7.68 (t, 1H,J=7.2 Hz), 7.42 (d, 2H, J=8 Hz), 7.14 (d, 2H, J=8 Hz), 4.70 (q, 1H, J=4Hz), 3.79-3.83 (m, 4H), 3.43 (t, 2H, J=7.2 Hz), 3.29-3.36 (m, 4H), 2.63(s, 3H), 2.13 (q, 2H, J=8 Hz), 1.99-2.02 (m, 2H).

Example 79.Isoxazolidin-2-yl-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=434 (M+1); ¹H NMR (DMSO-d₆) δ: 8.94 (m, 1H), 8.38 (d,1H, J=8 Hz), 7.75 (d, 1H, J=8.5 Hz), 7.53-7.60 (m, 4H), 7.10 (d, 2H, J=8Hz), 4.68 (q, 1H, J=4 Hz), 3.91 (s, 3H), 3.81 (m, 4H), 3.3 (m, 2H), 3.43(t, 2H, J=7 Hz), 2.14 (q, 2H, J=7 Hz), 2.10 (m, 2H), 1.57-1.66 (m, 2H).

Example 80.Isoxazolidin-2-yl-{4-[4-(7-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=418 (M+1); ¹H NMR (DMSO-d₆) δ: 9.24 (d, 1H, J=2 Hz),8.52 (d, 1H, J=2 Hz), 7.81-7.86 (m, 3H), 7.58 (d, 1H, J=7 Hz), 7.51 (t,1H, J=7 Hz), 7.15 (d, 2H, J=8 Hz), 4.70 (q, 1H, J=4 Hz), 3.77-3.83 (m,4H), 3.43 (t, 2H, J=7.5 Hz), 3.30-3.36 (m, 2H), 2.75 (s, 3H), 2.13 (q,2H, J=7 Hz), 1.99 (m, 2H), 1.59-1.65 (m, 2H).

Example 81.Isoxazolidin-2-yl-[4-(4-quinoxalin-2-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS m/z=405 (M+1); ¹H NMR (DMSO-d₆) δ: 9.55 (s, 1H), 8.30 (d,2H, J=8 Hz), 8.09 (m, 2H), 7.78-7.88 (m, 2H), 7.20 (d, 2H, J=8 Hz), 4.77(q, 1H, J=4 Hz), 3.77-3.83 (m, 4H), 3.43 (t, 2H, J=7 Hz), 3.34 (m, 2H),2.14 (q, 2H, J=7 Hz), 2.00 (m, 2H), 1.58-1.67 (m, 2H).

Example 82.4-[4-(4-Methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidmethoxyamide

Analysis: LCMS m/z=392 (M+1); ¹H NMR (DMSO-d₆ HCl salt) δ: 9.8 (s, 1H,D₂O exch), 8.99 (1H, br. s.), 8.43 (1H, d, J=8.3 Hz), 8.20 (1H, d, J=8.3Hz), 8.05 (1H, t, J=7.4 Hz), 7.88-7.99 (1H, m), 7.49 (2H, d, J=8.0 Hz),7.19 (2H, d, J=8.0 Hz), 4.70 (1H, br. s.), 3.63 (2H, d, J=12.8 Hz), 3.56(2H, s), 3.19 (2H, t, J=9.9 Hz), 2.80 (3H, s), 1.98 (2H, br. s.), 1.60(2H, d, J=8.3 Hz).

Example 83.4-[4-(4-Methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidmethoxymethyl-amide

Analysis: LCMS m/z=406 (M+1); 1H NMR (DMSO-d₆ HCl) δ: 9.05 (1H, s), 8.40(1H, d, J=8.5 Hz), 8.17-8.27 (1H, m), 7.95-8.03 (1H, m), 7.83-7.94 (1H,m), 7.42-7.55 (2H, m), 7.13-7.26 (2H, m), 4.65-4.83 (1H, m), 3.68-3.77(2H, m), 3.55 (3H, s), 3.23-3.34 (2H, m), 2.84 (3H, s), 2.78 (3H, s),1.98-2.08 (2H, m), 1.59-1.71 (2H, m).

Example 84.4-[4-(4-Methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidethylamide

Method A Example 73 using ethyl amine. Analysis: LCMS m/z=390 (M+1); ¹HNMR (DMSO-d₆) δ: 10.26 (1H, m; D₂O exch), 8.73 (1H, s), 8.19 (1H, d,J=8.3 Hz), 8.04 (1H, d, J=8.3 Hz), 7.77 (1H, td, J=7.5, 1.3 Hz),7.63-7.71 (1H, m), 7.40 (2H, d, J=8.8 Hz), 7.13 (2H, d, J=8.8 Hz), 6.51(1H, t, J=5.3 Hz), 4.63 (1H, dt, J=8.0, 4.2 Hz), 3.65-3.79 (2H, m),2.99-3.18 (4H, m), 2.63 (3H, s), 1.88-2.02 (2H, m), 1.45-1.62 (2H, m),1.02 (3H, t, J=7.2 Hz).

Example 85.4-[4-(8-Methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidmethylamide

Method A Example 73 using methyl amine in methanol. Analysis: LCMSm/z=392 (M+1); ¹H NMR (DMSO-d6 HCl salt) δ: 9.14 (1H, d, J=3.8 Hz), 8.96(1H, br. s.), 8.05 (1H, d, J=8.5 Hz), 7.92 (1H, d, J=7.8 Hz), 7.87 (1H,d, J=8.5 Hz), 7.69 (2H, d, J=8.8 Hz), 7.16 (2H, d, J=8.8 Hz), 4.61-4.70(1H, m), 3.74 (3H, s), 3.70 (2H, d, J=4.8 Hz), 3.13 (2H, ddd, J=13.2,9.7, 3.0 Hz), 2.58 (3H, s), 1.90-2.00 (2H, m), 1.47-1.59 (2H, m).

Example 86.4-[4-(8-Methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidethylamide

Method A Example 73 using ethyl amine HCl. Analysis: LCMS m/z=406 9M+1):¹H NMR (DMSO-d₆ HCl salt) δ: 9.17 (1H, d, J=4.0 Hz), 9.02 (1H, d, J=7.8Hz), 8.09 (1H, d, J=8.5 Hz), 7.94-8.03 (1H, m), 7.91 (1H, d, J=8.3 Hz),7.70 (2H, d, J=8.8 Hz), 7.17 (2H, d, J=8.8 Hz), 4.66 (1H, dt, J=8.2, 4.2Hz), 3.72 (5H, s), 3.01-3.21 (4H, m), 1.86-2.04 (2H, m), 1.45-1.61 (2H,m), 0.98-1.05 (3H, m).

Example 87.4-[4-(4-Methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidhydroxyamide

Analysis: LCMS m/z=378 (M+1); ¹H NMR (DMSO-d₆; HCl salt) δ: 8.71 (1H,s), 8.21 (1H, d, J=8.3 Hz), 8.05 (1H, d, J=8.5 Hz), 7.81 (1H, t, J=7.5Hz), 7.66-7.76 (1H, m), 7.41 (2H, d, J=8.3 Hz), 7.10-7.21 (2H, m), 4.66(1H, br. s.), 3.66 (2H, d, J=13.8 Hz), 3.17 (2H, t, J=9.9 Hz), 2.64 (3H,s), 1.89-2.05 (2H, m), 1.49-1.69 (2H, m).

Example 88.N-ethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide

Method A Example 73 using ethyl amine HCl. Analysis: LCMS m/z=390 (M+1);¹H NMR (DMSO-d₆; HCl salt) δ: 9.13 (d, J=3.8 Hz, 1H), 8.83 (br. s., 1H),8.07 (d, J=8.3 Hz, 1H), 7.85 (br. s., 1H), 7.68 (d, J=8.3 Hz, 1H), 7.40(d, J=8.3 Hz, 2H), 7.13 (d, J=8.5 Hz, 2H), 4.64 (d, J=3.8 Hz, 1H), 3.72(d, J=13.6 Hz, 2H), 3.02-3.20 (m, 4H), 2.72 (s, 3H), 1.95 (d, J=9.5 Hz,2H), 1.47-1.65 (m, 2H), 1.02 (t, J=7.2 Hz, 3H).

Method B. B 8-Methyl-7-[4-(piperidin-4-yloxy)-phenyl]-quinolinedihydrochloride (0.1 g, 0.31 mmol) and DIEA (0.16 mL, 0.94 mmol) in DCM(2 mL) was added isocyanatoethane (0.27 g, 0.30 mL, 3.8 mmol) thenstirred at 70° C. for 2 h. The reaction was concentrated, dissolved inEtOAc and washed with 1N Na₂CO₃ and brine and dried (MgSO₄). The productwas chromatographed on ISCO (24 g silica gel, 50-100% EtOAC-hexanes) togive an oil. The HCl salt (synthesized from 1N HCl-ether and DCM) wascrystallized from DCM-ether to give a yellow solid (69%).

Example 89N,N-dimethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide

To 8-methyl-7-[4-(piperidin-4-yloxy)-phenyl]-quinoline dihydrochloride(0.150 g, 0.383 mmol) in DCM (4 mL) was added TEA (0.214 mL, 1.53 mmol)and N,N-dimethylcarbamoyl chloride (0.0824 g, 0.767 mmol). Afterstirring at rt for 2 h, the mixture was concentrated, washed with 1NNa₂CO₃ and brine then dried over MgSO₄. The product was purified by ISCO(12 g silica gel, EtOAc/hexanes 40-80%) to give an oil. The HCl salt wassynthesized by adding 0.5 mL of a 2M HCl ether solution to a DCMsolution of base. The salt was crystallized from DCM-ether to give ayellow solid (87%). Analysis: LCMS m/z=390 (M+1); ¹H NMR (DMSO-d6) δ:9.15 (d, J=3.5 Hz, 1H), 8.89 (d, J=7.3 Hz, 1H), 8.11 (d, J=8.5 Hz, 1H),7.90 (dd, J=7.8, 4.5 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.41 (d, J=8.5 Hz,2H), 7.14 (d, J=8.5 Hz, 2H), 4.66 (dt, J=8.0, 4.2 Hz, 1H), 3.30-3.62 (m,2H), 3.04 (ddd, J=12.9, 9.5, 2.9 Hz, 2H), 2.75 (s, 6H), 2.73 (s, 3H),1.91-2.07 (m, 2H), 1.52-1.78 (m, 2H).

Example 90. Ethyl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate

To 8-methyl-7-[4-(piperidin-4-yloxy)-phenyl]-quinoline 2HCl (0.150 g,0.383 mmol) in DCM (4 mL) was added TEA (0.214 mL, 1.53 mmol) and ethylchloroformate (0.0832 g, 0.767 mmol). After stirring at rt for 2 h, themixture was concentrated, washed with 1N Na₂CO₃ and brine then driedover MgSO₄. The product was purified by ISCO (12 g silica gel,EtOAc/hexanes 40-80%) to give oil. The HCl salt (synthesized from 2NHCl-ether and DCM) was crystallized from DCM-ether-hexanes to give alight yellow solid (73%). Analysis: LCMS m/z=391 (M+1); ¹H NMR (DMSO-d₆)δ: 9.14 (d, J=4.3 Hz, 1H), 8.87 (br. s., 1H), 8.09 (d, J=8.3 Hz, 1H),7.88 (d, J=4.8 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.41 (d, J=8.8 Hz, 2H),7.14 (d, J=8.5 Hz, 2H), 4.64-4.78 (m, 1H), 4.06 (q, J=7.1 Hz, 2H),3.68-3.84 (m, 2H), 3.28 (t, J=9.5 Hz, 2H), 2.67-2.80 (m, 3H), 1.98 (d,J=7.3 Hz, 2H), 1.60 (dtd, J=12.7, 8.6, 3.9 Hz, 2H), 1.20 (t, J=7.0 Hz,3H).

Example 91.N-methoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide

To 8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline 2HCl (0.15 g, 0.3833mmol) in DCM (4 mL) was added TEA (0.214 mL, 1.533 mmol) and triphosgene(0.1138 g, 0.3833 mmol) on an ice bath, stirred for 1 h thenconcentrated. The residue in DCM (4 mL) was added TEA (0.214 mL, 1.533mmol) and O-methylhydroxylamine HCl (0.06403 g, 0.7667 mmol) then heatedat 70° C. for 2 h. The mixture was concentrated, washed with 1N Na₂CO₃and brine then dried over MgSO₄. The product was purified by ISCO (12 gsilica gel, EtOAc/hexanes 40-90% over 5 min) to give and oil. The HClsalt (0.5 mL 2N HCl-ether added to DCM solution of base) wascrystallized from DCM-ether to give a light yellow solid (67%).Analysis: LCMS m/z=392 (M+1); ¹H NMR (DMSO-d₆) δ: 9.75 (br. s., 1H),9.08 (d, J=3.8 Hz, 1H), 8.70 (br. s., 1H), 8.02 (d, J=8.0 Hz, 1H), 7.77(br. s., 1H), 7.63 (d, J=8.5 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H), 7.12 (d,J=8.8 Hz, 2H), 4.60-4.71 (m, 1H), 3.59-3.72 (m, 2H), 3.54 (s, 3H),3.06-3.21 (m, 2H), 2.67-2.76 (m, 3H), 1.96 (d, J=10.3 Hz, 2H), 1.47-1.64(m, 2H)

Example 92.N-Isopropyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide

This example was synthesized using isopropyl amine by the procedure forExample 91. Analysis: LCMS m/z=404 (M+1); ¹H NMR (DMSO-d₆; HCl salt) δ:9.08 (d, J=3.3 Hz, 1H), 8.70 (br. s., 1H), 8.01 (d, J=8.3 Hz, 1H), 7.77(br. s., 1H), 7.63 (d, J=8.3 Hz, 1H), 7.39 (d, J=8.8 Hz, 2H), 7.12 (d,J=8.5 Hz, 2H), 6.20 (br. s., 1H), 4.63 (dt, J=7.7, 4.0 Hz, 2H),3.69-3.81 (m, 3H), 3.11 (t, J=9.8 Hz, 2H), 2.70 (s, 3H), 1.95 (d, J=10.3Hz, 2H), 1.46-1.59 (m, 2H), 1.07 (d, J=6.5 Hz, 6H).

Example 93.N-ethoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide

This example was synthesized using O-ethylhydroxylamine HCl. Analysis:LCMS m/z=406 (M+1); ¹H NMR (DMSO-d₆; HCl salt) δ: 9.66 (br. s., 1H),9.07 (d, J=3.3 Hz, 1H), 8.67 (br. s., 1H), 8.00 (d, J=8.3 Hz, 1H), 7.76(br. s., 1H), 7.61 (d, J=8.5 Hz, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.12 (d,J=8.5 Hz, 2H), 4.65 (dt, J=8.0, 3.9 Hz, 1H), 3.75 (q, J=7.0 Hz, 2H),3.69-3.58 (m, 2H), 3.22-3.06 (m, 2H), 2.72-2.68 (m, 3H), 1.96 (d, J=12.5Hz, 2H), 1.62-1.50 (m, 2H), 1.13 (t, J=7.0 Hz, 3H).

Example 94.[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-pyrrolidin-1-yl-methanone

This example was synthesized using pyrrolidine-1-carbonyl chloride.Analysis: LCMS m/z=390 (M+1); ¹H NMR (DMSO-d₆; HCl salt) δ: 9.15 (d,J=3.5 Hz, 1H), 8.89 (d, J=7.3 Hz, 1H), 8.11 (d, J=8.5 Hz, 1H), 7.90 (dd,J=7.8, 4.5 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.41 (d, J=8.5 Hz, 2H), 7.14(d, J=8.5 Hz, 2H), 4.66 (dt, J=8.0, 4.2 Hz, 1H), 3.30-3.62 (m, 2H), 3.04(ddd, J=12.9, 9.5, 2.9 Hz, 2H), 2.75 (s, 6H), 2.73 (s, 3H), 1.91-2.07(m, 2H), 1.52-1.78 (m, 2H).

Example 95.N-methyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide

This example was synthesized using aqueous methylamine and triphosgene.Analysis: LCMS m/z=376 (M+1); ¹H NMR (DMSO-d₆; HCl salt) δ: 9.10 (d,J=3.3 Hz, 1H), 8.74 (br. s., 1H), 8.03 (d, J=8.8 Hz, 1H), 7.79 (br. s.,1H), 7.64 (d, J=8.5 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.5 Hz,2H), 4.63 (dd, J=7.8, 4.3 Hz, 2H), 3.71 (d, J=13.6 Hz, 2H), 3.20-3.04(m, 2H), 2.71 (s, 3H), 2.58 (s, 3H), 2.04-1.88 (m, 2H), 1.61-1.48 (m,2H).

Example 96.4-[4-(8-methyl-7-quinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide

This example was synthesized using n-propylamine and triphosgene.Analysis: LCMS m/z=404 (M+1); ¹H NMR (DMSO-d6; HCl salt) δ: 9.13 (d,J=3.5 Hz, 1H), 8.85 (br. s., 1H), 8.08 (d, J=8.3 Hz, 1H), 7.87 (br. s.,1H), 7.69 (d, J=8.5 Hz, 1H), 7.41 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.5 Hz,2H), 4.64 (dt, J=8.3, 4.1 Hz, 1H), 3.80-3.66 (m, 2H), 3.23-3.07 (m, 2H),2.99 (t, J=7.2 Hz, 2H), 2.72 (s, 3H), 1.95 (d, J=9.8 Hz, 2H), 1.60-1.49(m, 2H), 1.46-1.37 (m, 2H), 0.84 (t, J=7.4 Hz, 3H).

Example 97. 4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide

This example was synthesized using ammonia in methanol and triphosgene.Analysis: LCMS m/z=362 (M+1); ¹H NMR (DMSO-d₆; HCl salt) δ: 8.97 (dd,J=4.1, 1.9 Hz, 1H), 8.36 (dd, J=8.2, 1.6 Hz, 1H), 7.85 (d, J=8.3 Hz,1H), 7.55 (dd, J=8.3, 4.3 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.37 (d,J=8.5 Hz, 2H), 7.10 (d, J=8.8 Hz, 2H), 5.96 (s, 2H, D₂O exch), 4.67-4.59(m, 1H), 3.71 (d, J=14.3 Hz, 2H), 3.29 (s, 1H), 3.18-3.07 (m, 2H), 2.68(s, 3H), 1.95 (d, J=9.0 Hz, 2H).

Example 98.[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(1-piperidyl)methanone

This example was synthesized using piperidine-1-carbonyl chloride.Analysis: LCMS m/z=430 (M+1); ¹H NMR (DMSO-d₆; HCl salt) δ: 9.08 (d,J=3.3 Hz, 1H), 8.69 (br. s., 1H), 8.01 (d, J=8.5 Hz, 1H), 7.77 (br. s.,1H), 7.62 (d, J=8.5 Hz, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.19-7.08 (m, 2H),4.64 (dt, J=8.1, 4.1 Hz, 1H), 3.49-3.40 (m, 2H), 3.15-3.10 (m, 4H), 3.05(ddd, J=12.9, 9.5, 3.1 Hz, 2H), 2.70 (s, 3H), 2.06-1.93 (m, 2H),1.70-1.58 (m, 2H), 1.57-1.46 (m, 6H).

Example 99.[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-morpholinomethanone

This example was synthesized using morpholine-4-carbonyl chloride.Analysis: LCMS m/z=432 (M+1); ¹H NMR (DMSO-d₆; HCl salt) δ: 9.13 (d,J=3.5 Hz, 1H), 8.82 (d, J=5.8 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.92-7.79(m, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.41 (d, J=8.5 Hz, 2H), 7.14 (d, J=8.8Hz, 2H), 4.67 (dt, J=7.9, 4.1 Hz, 1H), 3.61-3.54 (m, 4H), 3.53-3.45 (m,2H), 3.20-3.04 (m, 6H), 2.72 (s, 3H), 2.00 (d, J=12.0 Hz, 2H), 1.73-1.57(m, 2H).

The following examples were synthesized using representative proceduresdescribed above for example 3 or example 33.

Example 100.Cyclopropyl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone,HCl

The product was isolated as a yellow solid. Analysis: mp: 170-173° C.;LCMS m/z=373 (M+1); ¹HNMR (DMSO-d₆) δ: 9.51 (d, J=2 Hz, 1H), 9.15 (s,1H), 8.29-8.24 (m, 2H), 8.00-7.95 (m, 3H), 7.87-7.83 (m, 1H), 7.23 (m,2H), 4.79 (m, 1H), 4.08-3.82 (m, 2H), 3.66-3.49 (m, 1H), 3.39-3.22 (m,1H), 2.13-1.87 (m, 3H), 1.75-1.46 (m, 2H), 0.79-0.65 (m, 4H).

Example 101.Cyclobutyl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone,HCl

The product was isolated as a yellow solid. Analysis: mp: 164-166° C.;LCMS m/z=387 (M+1); ¹HNMR (DMSO-d₆) δ: 9.53 (d, J=2 Hz, 1H), 9.17 (s,1H), 8.31-8.24 (m, 2H), 8.01-7.84 (m, 4H), 7.21 (m, 2H), 4.75 (m, 1H),3.94-3.82 (m, 1H), 3.66-3.53 (m, 1H), 3.44-3.21 (m, 3H), 2.25-2.03 (m,4H), 2.02-1.83 (m, 3H), 1.80-1.68 (m, 1H), 1.64-1.47 (m, 2H).

Example 102.Cyclopentyl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone, 2HCl

The product was isolated as an off-white solid. Analysis: mp: 145-147°C.; LCMS m/z=401 (M+1); ¹HNMR (400 MHz, DMSO-d₆) δ: 9.52 (m, 1H), 9.16(s, 1H), 8.27 (m, 2H), 8.02-7.82 (m, 4H), 7.22 (m, 2H), 4.77 (m, 1H),3.97-3.74 (m, 2H), 3.48-3.21 (m, 2H), 3.02 (m, 1H), 2.08-1.88 (m, 2H),1.84-1.45 (m, 10H).

Example 103.[4-(4-Quinolin-3-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydrofuran-2-yl-methanone,HCl

The product was isolated as a light-brown solid. Analysis: LCMS m/z=403(M+1); ¹HNMR (400 MHz, DMSO-d₆) δ: 9.52 (m, 1H), 9.16 (s, 1H), 8.26 (m,2H), 7.99 (m, 1H), 7.93 (m, 2H), 7.85 (m, 1H), 7.22 (m, 2H), 4.78 (m,1H), 4.70 (m, 1H), 3.95-3.70 (m, 4H), 3.66-3.07 (m, 2H), 2.12-1.75 (m,4H), 1.73-1.45 (m, 2H), 1.33-1.21 (m, 2H).

Example 104.[4-(4-Quinolin-3-yl-phenoxy)-piperidin-1-yl]-(S)-tetrahydrofuran-2-yl-methanone,HCl

The product was isolated as a light-brown solid. Analysis: LCMS m/z=403(M+1); ¹HNMR (400 MHz, DMSO-d₆) δ: 9.53 (m, 1H), 9.19 (s, 1H), 8.28 (m,2H), 8.00 (m, 1H), 7.94 (m, 2H), 7.86 (m, 1H), 7.22 (m, 2H), 4.78 (m,1H), 4.70 (m, 1H), 3.95-3.70 (m, 4H), 3.53-3.22 (m, 2H), 2.12-1.74 (m,4H), 1.72-1.48 (m, 2H), 1.33-1.15 (m, 2H).

Example 105.2-Methoxy-1-[4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-ethanone, 2HCl

The product was isolated as a tan solid. Analysis: LCMS m/z=377 (M+1);¹HNMR (400 MHz, DMSO-d₆) δ: 9.53 (m, 1H), 9.20 (s, 1H), 8.29 (m, 2H),8.00 (m, 1H), 7.94 (m, 2H), 7.87 (m, 1H), 7.22 (m, 2H), 4.78 (m, 1H),4.11 (m, 2H), 3.87 (m, 1H), 3.66 (m, 1H), 3.32 (m, 2H), 3.30 (s, 3H),1.99 (m, 2H), 1.62 (m, 2H).

Example 106.[4-(4-Quinolin-3-yl-phenoxy)-piperidin-1-yl]-(tetrahydropyran-2-yl)-methanone,2HCl

The product was isolated as a tan solid. Analysis: LCMS m/z=417 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ: 9.54-9.58 (1H, m), 9.22-9.26 (1H, m),8.25-8.33 (2H, m), 7.99-8.06 (1H, m), 7.93-7.97 (2H, m), 7.85-7.91 (1H,m), 7.20-7.25 (2H, m), 4.74-4.83 (1H, m), 4.12-4.19 (1H, m), 3.76-3.92(3H, m), 3.56-3.65 (1H, m), 3.42-3.53 (2H, m), 3.08-3.16 (1H, m),1.88-2.08 (2H, m), 1.79-1.86 (1H, m), 1.43-1.66 (7H, m), 1.24-1.32 (12H,m).

Example 107.[4-(4-Quinolin-3-yl-phenoxyl)-piperidin-1-yl]-(tetrahydrofuran-3-yl)-methanone,2HCl

Analysis: LCMS m/z=403 (M+1); ¹HNMR (400 MHz, DMSO-d₆) δ: 9.53 (m, 1H),9.19 (s, 1H), 8.28 (m, 2H), 8.00 (m, 1H), 7.94 (m, 2H), 7.86 (m, 1H),7.22 (m, 2H), 4.78 (m, 1H), 3.96-3.55 (m, 4H), 3.50-3.27 (m, 3H),2.10-1.89 (m, 4H), 1.70-1.50 (m, 2H), 1.33-1.22 (m, 2H).

Example 108.(R)-2-Methoxy-1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one,2HCl

Analysis: LCMS m/z=391 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.22-9.25(1H, m), 8.57-8.59 (1H, m), 8.01-8.06 (2H, m), 7.81-7.86 (2H, m),7.72-7.78 (1H, m), 7.60-7.67 (1H, m), 7.15-7.20 (2H, m), 4.70-4.79 (1H,m), 4.20-4.29 (1H, m), 3.80-3.98 (2H, m), 3.38-3.50 (1H, m), 3.33-3.38(1H, m), 3.22 (3H, s), 1.92-2.07 (2H, m), 1.51-1.73 (2H, m), 1.23 (3H,d, J=6.8 Hz).

Example 109.(S)-2-Methoxy-1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one,2HCl

Analysis: LCMS m/z=391 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.22-9.25(1H, m), 8.57-8.60 (1H, m), 8.01-8.06 (2H, m), 7.81-7.86 (2H, m),7.72-7.78 (1H, m), 7.60-7.66 (1H, m), 7.15-7.20 (2H, m), 4.71-4.79 (1H,m), 4.20-4.28 (1H, m), 3.81-3.97 (2H, m), 3.39-3.50 (1H, m), 3.33-3.38(1H, m), 3.22 (3H, s), 1.93-2.08 (2H, m), 1.51-1.71 (2H, m), 1.23 (3H,d, J=6.5 Hz).

Example 110.2-Hydroxy-1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-ethanone, 2HCl

The product was isolated as a light-brown solid. Analysis: LCMS m/z=363(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.23 (1H, d, J=2.5 Hz), 8.58 (1H, d,J=2.3 Hz), 8.03 (2H, d, J=8.1 Hz), 7.84 (2H, d, J=8.8 Hz), 7.70-7.78(1H, m), 7.60-7.67 (1H, m), 7.17 (2H, d, J=7.9 Hz), 4.70-4.79 (1H, m),4.53 (1H, t, J=5.4 Hz), 4.12 (2H, d, J=5.5 Hz), 3.83-3.94 (1H, m),3.55-3.67 (1H, m), 3.34-3.39 (1H, m), 3.24-3.31 (1H, m), 1.92-2.07 (2H,m), 1.52-1.72 (2H, m).

Example 111.[4-(4-Quinolin-3-yl-phenoxy)-piperidin-1-yl]-(tetrahydropyran-2-yl)-methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=399(M+1); ¹HNMR (400 MHz, DMSO-d₆) δ: 9.53 (s, 1H), 9.18 (s, 1H), 8.27 (m,2H), 8.06-7.81 (m, 5H), 7.23 (m, 2H), 7.01 (m, 1H), 6.64 (m, 1H), 4.84(m, 1H), 3.99 (m, 2H), 3.58 (m, 2H), 2.06 (m, 2H), 1.70 (m, 2H).

Example 112. 1-[4-(4-Quinolin-3-yl-phenoxy)-piperidin-1-yl]-ethanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=347(M+1); ¹HNMR (400 MHz, DMSO-d₆) δ: 9.57 (m, 1H), 9.26 (s, 1H), 8.32 (m,2H), 8.03 (m, 1H), 7.95 (m, 2H), 7.89 (m, 1H), 7.23 (m, 2H), 4.77 (m,1H), 3.92-3.82 (m, 1H), 3.76-3.66 (m, 1H), 3.44-3.34 (m, 1H), 3.32-3.23(m, 1H), 2.03 (s, 3H), 2.07-1.87 (m, 2H), 1.72-1.48 (m, 2H).

Example 113.2-Methyl-1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=375(M+1); ¹HNMR (400 MHz, DMSO-d₆) δ: 9.51 (m, 1H), 9.14 (s, 1H), 8.26 (m,2H), 8.02-7.80 (m, 4H), 7.21 (m, 2H), 4.77 (m, 1H), 3.97-3.73 (m, 2H),3.49-3.21 (m, 2H), 2.91 (m, 1H), 2.09-1.89 (m, 2H), 1.71-1.46 (m, 2H),1.01 (d, J=6.7 Hz, 6H).

Example 114.2,2-Dimethyl-1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=389(M+1); ¹HNMR (400 MHz, DMSO-d₆) δ: 9.55 (m, 1H), 9.15 (s, 1H), 8.26 (m,2H), 7.98 (m, 1H), 7.94 (m, 2H), 7.85 (m, 1H), 7.21 (m, 2H), 4.78 (m,1H), 3.98-3.86 (m, 2H), 3.45-3.34 (m, 2H), 2.05-1.94 (m, 2H), 1.65-1.53(m, 2H), 1.22 (s, 9H).

Example 115.(2-Methyltetrahydrofuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=417(M+1); ¹HNMR (400 MHz, DMSO-d₆) δ: 9.52 (m, 1H), 9.17 (s, 1H), 8.26 (m,2H), 7.99 (m, 1H), 7.94 (m, 2H), 7.85 (m, 1H), 7.21 (m, 2H), 4.77 (m,1H), 4.41-3.11 (m, 6H), 2.72-2.61 (m, 1H), 2.08-1.47 (m, 7H), 1.40 (s,3H).

Example 116.(2-Methyl-1,3-dioxolan-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone,HCl

The product was isolated as a tan solid. Analysis: LCMS m/z=419 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ: 9.22-9.26 (1H, m), 8.56-8.60 (1H, m),8.01-8.07 (2H, m), 7.80-7.88 (2H, m), 7.72-7.79 (1H, m), 7.60-7.67 (1H,m), 7.14-7.22 (2H, m), 4.70-4.84 (1H, m), 3.98-4.04 (1H, m), 3.92-3.98(2H, m), 3.77-3.86 (2H, m), 3.48-3.65 (1H, m), 3.35-3.48 (2H, m), 3.33(3H, s), 1.95-2.08 (2H, m), 1.55-1.76 (2H, m).

Example 117.2-Methanesulfonyl-1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-ethanone,HCl

The product was isolated as a tan solid. Analysis: LCMS m/z=425 (M+1);¹HNMR (400 MHz, DMSO-d₆) δ: 9.51 (m, 1H), 9.15 (s, 1H), 8.26 (m, 2H),7.98 (m, 1H), 7.94 (m, 2H), 7.85 (m, 1H), 7.23 (m, 2H), 4.80 (m, 1H),4.51 (s, 2H), 3.96-3.77 (m, 2H), 3.57-3.34 (m, 2H), 3.12 (s, 3H),2.11-1.92 (m, 2H), 1.79-1.52 (m, 2H).

Example 118.(1,1-Dioxidotetrahydrothiophen-2-yl)(4-(4-(quinolin-3-yl)phenoxy)piperidin-1-yl)methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=451(M+1); ¹HNMR (400 MHz, DMSO-d₆) δ: 9.51 (s, 1H), 9.15 (s, 1H), 8.26 (m,2H), 7.98 (m, 1H), 7.94 (m, 2H), 7.85 (m, 1H), 7.23 (m, 2H), 4.82 (m,1H), 4.67 (m, 1H), 4.08-3.79 (m, 2H), 3.64-3.44 (m, 2H), 3.39-3.19 (m,2H), 3.14-3.00 (m, 1H), 2.26-1.46 (m, 7H).

Example 119.(3,3-Difluorocyclobutyl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone

The product was isolated as an off-white solid. Analysis: LCMS m/z=423(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.21-9.25 (1H, m), 8.56-8.60 (1H,m), 8.01-8.06 (2H, m), 7.81-7.86 (2H, m), 7.72-7.78 (1H, m), 7.60-7.67(1H, m), 7.14-7.20 (2H, m), 4.69-4.78 (1H, m), 3.84-3.93 (1H, m),3.60-3.70 (1H, m), 3.33-3.39 (2H, m), 3.23-3.31 (1H, m), 2.73-2.86 (4H,m), 1.91-2.04 (2H, m), 1.53-1.69 (2H, m).

Example 120.(R)-5-[4-(4-Quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-dihydrofuran-2-one,HCl

LCMS m/z=tan solid. Analysis: LCMS m/z=417 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ: 9.48-9.51 (1H, m), 9.08-9.13 (1H, m), 8.20-8.28 (2H, m),7.90-8.00 (3H, m), 7.80-7.86 (1H, m), 7.20-7.26 (2H, m), 5.51-5.57 (1H,m), 4.75-4.86 (1H, m), 3.68-3.97 (2H, m), 3.28-3.52 (2H, m), 2.39-2.49(3H, m), 2.14-2.26 (1H, m), 1.92-2.11 (2H, m), 1.56-1.78 (2H, m).

Example 121.(3-Methylfuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=413(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.51-9.55 (1H, m), 9.14-9.20 (1H,m), 8.23-8.32 (2H, m), 7.92-8.04 (3H, m), 7.82-7.89 (1H, m), 7.67-7.72(1H, m), 7.20-7.27 (2H, m), 6.48-6.53 (1H, m), 4.78-4.88 (1H, m),3.83-3.96 (2H, m), 3.43-3.55 (2H, m), 2.16 (3H, s), 2.00-2.11 (2H, m),1.62-1.75 (2H, m).

Example 122.(3,5-Dimethylfuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=427(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.51-9.56 (1H, m), 9.15-9.21 (1H,m), 8.22-8.34 (2H, m), 7.92-8.04 (3H, m), 7.82-7.90 (1H, m), 7.20-7.27(2H, m), 6.10-6.14 (1H, m), 4.78-4.87 (1H, m), 3.86-3.96 (2H, m),3.42-3.53 (2H, m), 2.27 (3H, s), 2.11 (3H, s), 2.00-2.09 (2H, m),1.61-1.73 (2H, m).

Example 123.Oxazol-2-yl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone; HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=400(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.50-9.56 (1H, m), 9.14-9.21 (1H,m), 8.22-8.35 (3H, m), 7.91-8.03 (3H, m), 7.82-7.89 (1H, m), 7.44-7.49(1H, m), 7.20-7.28 (2H, m), 4.81-4.90 (1H, m), 4.21-4.32 (1H, m),3.94-4.04 (1H, m), 3.81-3.91 (1H, m), 3.54-3.63 (1H, m), 2.03-2.13 (2H,m), 1.67-1.81 (2H, m).

Example 124.Isoxazol-3-yl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=400(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.51-9.55 (1H, m), 9.16-9.20 (1H,m), 9.09-9.12 (1H, m), 8.23-8.33 (2H, m), 7.92-8.03 (3H, m), 7.83-7.89(1H, m), 7.21-7.27 (2H, m), 6.85-6.88 (1H, m), 4.82-4.90 (1H, m),3.96-4.06 (1H, m), 3.74-3.83 (1H, m), 3.47-3.63 (2H, m), 1.99-2.13 (2H,m), 1.65-1.79 (2H, m).

Example 125.Isothiazol-3-yl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=416(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.51-9.55 (1H, m), 9.14-9.20 (2H,m), 8.23-8.32 (2H, m), 7.91-8.03 (3H, m), 7.82-7.89 (1H, m), 7.60-7.64(1H, m), 7.21-7.27 (2H, m), 4.80-4.89 (1H, m), 3.98-4.07 (1H, m),3.80-3.89 (1H, m), 3.48-3.61 (2H, m), 1.99-2.14 (2H, m), 1.64-1.78 (2H,m).

Example 126.[4-(4-Quinolin-3-yl-phenoxy)-piperidin-1-yl]-(tetrahydrofuran-2-yl)-methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=403(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.47-9.51 (1H, m), 9.08-9.12 (1H,m), 8.20-8.27 (2H, m), 7.89-8.00 (3H, m), 7.80-7.86 (1H, m), 7.19-7.25(2H, m), 4.73-4.82 (1H, m), 4.66-4.73 (1H, m), 4.27-4.32 (1H, m),3.75-3.82 (4H, m), 1.96-2.06 (3H, m), 1.80-1.87 (4H, m), 1.53-1.68 (2H,m).

Example 127.Phenyl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone, HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=409(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.46-9.51 (1H, m), 9.05-9.10 (1H,m), 8.18-8.27 (2H, m), 7.89-7.99 (3H, m), 7.78-7.85 (1H, m), 7.40-7.49(5H, m), 7.19-7.25 (2H, m), 4.77-4.85 (1H, m), 3.91-4.11 (1H, m),3.43-3.64 (2H, m), 3.26-3.43 (1H, m), 1.90-2.14 (2H, m), 1.60-1.78 (2H,m).

Example 128.(2,5-Dimethylphenyl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=437(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.46-9.51 (1H, m), 9.07-9.12 (1H,m), 8.20-8.28 (2H, m), 7.89-8.00 (3H, m), 7.80-7.86 (1H, m), 7.18-7.24(2H, m), 7.03-7.12 (3H, m), 4.75-4.84 (1H, m), 3.95-4.16 (1H, m),3.32-3.62 (2H, m), 3.13-3.24 (1H, m), 2.29 (3H, s), 2.20 (3H, s),2.02-2.13 (1H, m), 1.85-1.97 (1H, m), 1.64-1.77 (1H, m), 1.48-1.62 (1H,m).

Example 129.[3-(1H-Imidazol-2-yl)-phenyl]-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=475(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 15.02-15.51 (1H, m), 9.44-9.48 (1H,m), 9.01-9.06 (1H, m), 8.18-8.31 (4H, m), 7.89-7.97 (3H, m), 7.84 (3H,s), 7.68-7.76 (2H, m), 7.20-7.26 (2H, m), 4.80-4.89 (1H, m), 3.96-4.13(1H, m), 3.48-3.66 (2H, m), 3.31-3.48 (1H, m), 2.00-2.18 (2H, m),1.66-1.81 (2H, m).

Example 130.[3-(1H-Benzimidazol-2-yl)-phenyl]-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=525(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.48-9.51 (1H, m), 9.09-9.13 (1H,m), 8.44-8.51 (2H, m), 8.21-8.30 (2H, m), 7.91-8.00 (3H, m), 7.78-7.89(5H, m), 7.54-7.61 (2H, m), 7.21-7.27 (2H, m), 4.83-4.91 (1H, m),4.00-4.14 (2H, m), 3.51-3.69 (2H, m), 3.34-3.50 (1H, m), 2.00-2.18 (2H,m), 1.70-1.83 (2H, m).

Example 131.N-Methoxy-4-[4-(8-methoxy-7-quinolyl)phenoxy]piperidine-1-carboxamide,HCl

This example was synthesized using the procedure for example 91 startingwith 8-methoxy-7-[4-(4-piperidyloxy)phenyl]quinoline 2HCl to give ayellow solid. Analysis: LCMS m/z=408 (M+1); 1H NMR (400 MHz, DMSO-d6) δ:9.68-9.86 (1H, m), 9.11-9.18 (1H, m), 8.90-9.02 (1H, m), 8.02-8.12 (1H,m), 7.83-7.98 (2H, m), 7.69 (2H, d, J=8.5 Hz), 7.17 (2H, d, J=8.8 Hz),4.61-4.73 (1H, m), 3.74 (3H, s), 3.59-3.70 (2H, m), 3.55 (3H, s),3.08-3.22 (2H, m), 1.92-1.99 (2H, m), 1.49-1.64 (2H, m).

Example 132.1-[4-(5-Quinolin-3-yl-pyridin-2-yloxy)-piperidin-1-yl]-propan-1-one, HCl

Step 1. 4-(5-Bromopyridin-2-yloxy)-piperidine-1-carboxylic acidtert-butyl ester

To a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester(5.75 g, 28.6 mmol) in DMF (50 mL) was sodium hydride, 60% disp. inmineral oil (1.35 g, 33.8 mmol) in portion. After stirred for 10 min, tothe reaction was added 5-bromo-2-chloro-pyridine (5.00 g, 26.0 mmol)followed by K₂CO₃ (3.59 g, 26.0 mmol). The reaction was heated at 105°C. for 16 h and cooled to room temp. It was carefully quenched with H₂O(100 mL), extracted with EtOAc (3×300 mL). The combined organic layerswere washed with H₂O, brine, dried (Na₂SO₄) and concentrated. Theresidue was chromatography on silica gel (0-20% EtOAc/Hexanes) to give awhite solid 8.30 g (89%).

Step 2. 4-(5-Quinolin-3-yl-pyridin-2-yloxy)-piperidine-1-carboxylic acidtert-butyl ester

A flask charged with 4-(5-bromopyridin-2-yloxy)-piperidine-1-carboxylicacid tert-butyl ester (750 mg, 2.1 mmol), 3-quinolineboronic acid (540mg, 3.1 mmol), palladium acetate (47 mg, 0.21 mmol), triphenylphosphine(110 mg, 0.42 mmol), 1.0 M of sodium carbonate in water (8.4 mL, 8.4mmol), 1,4-dioxane (5 mL), and DMF (10 mL) was flashed with N₂ for 15min. After stirred at 85° C. for 16 h, the reaction was cooled to roomtemp and added EtOAc (100 mL), washed with 1M Na₂CO₃ solution (30 mL),H₂O, brine, dried (Na₂SO₄), and concentrated. The residue waschromatography on silica gel (0-70% EtOAc/Hexanes) to give a grayishsolid 723 mg (85%).

Step 3. 3-[6-(Piperidin-4-yloxy)-pyridin-3-yl]-quinoline, 2HCl

To a solution of4-(5-quinolin-3-yl-pyridin-2-yloxy)-piperidine-1-carboxylic acidtert-butyl ester (701 mg, 1.73 mmol) in DCM (25 mL) was added 4.0 M ofHCl in 1,4-dioxane (4.32 mL, 17.3 mmol) and stirred at room temperaturefor 24 h. The resulted white precipitate was collected by filtration,washed with DCM, dried to give a white solid 626 mg (96%).

Step 4

To a solution of 3-[6-(piperidin-4-yloxy)-pyridin-3-yl]-quinoline, 2HCl(100 mg, 0.3 mmol) and Et₃N in DCM (8 mL) was added propanoyl chloride(50 μL, 0.6 mmol). After 15 min, the reaction was diluted with DCM (50mL), washed with H₂O (2×20 mL), sat. NaHCO₃, brine, dried (Na₂SO₄), andconcentrated. The residue was purified by chromatography on silica gel(0-100 EtOAc/Hexanes) and the isolated product was dissolved in a mixedsolvent MeOH-DCM (1:1), treated with 1.2 eq. of 2 M HCl Et₂O solution,and concentrated. It was stripped with small amount of MeOH-DCM (1:1)several times, dried to give a tan solid 88 mg (80%). Analysis: LCMSm/z=362 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.63 (1H, d, J=2.3 Hz), 9.35(1H, s), 8.81 (1H, d, J=2.8 Hz), 8.27-8.45 (3H, m), 8.07 (1H, ddd,J=8.5, 7.1, 1.3 Hz), 7.87-7.96 (1H, m), 7.05 (1H, d, J=8.8 Hz), 5.33(1H, tt, J=8.2, 3.9 Hz), 3.89-4.01 (1H, m), 3.69-3.81 (1H, m), 3.32-3.44(1H, m), 3.20-3.32 (1H, m), 2.36 (2H, q, J=7.4 Hz), 1.94-2.12 (2H, m),1.52-1.76 (2H, m), 1.01 (3H, t, J=7.4 Hz).

The following compounds were synthesized using the procedures employedin Example 132 above.

Example 133.2-Methyl-1-[4-(5-quinolin-3-yl-pyridin-2-yloxy)-piperidin-1-yl]-propan-1-one,HCl

The product was isolated as an off-white solid. Analysis: LCMS m/z=376(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.62 (1H, d, J=2.0 Hz), 9.33 (1H,s), 8.81 (1H, d, J=2.3 Hz), 8.26-8.42 (3H, m), 8.09-8.10 (1H, m),7.89-7.95 (1H, m), 7.05 (1H, d, J=8.5 Hz), 5.34 (1 H, tt, J=8.2, 3.9Hz), 3.91-4.02 (1H, m), 3.78-3.88 (1H, m), 3.37-3.50 (1H, m), 3.20-3.32(1H, m), 2.92 (1H, quin, J=6.8 Hz), 1.94-2.15 (2H, m), 1.52-1.76 (2H,m), 0.97-1.06 (6H, m).

Example 134.Cyclopropyl-[4-(5-quinolin-3-yl-pyridin-2-yloxy)-piperidin-1-yl]-methanone,HCl

The product was isolated as a tan solid. Analysis: LCMS m/z=374 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ: 9.57 (1H, d, J=2.3 Hz), 9.22 (1H, s), 8.80(1H, d, J=2.0 Hz), 8.31-8.36 (2H, m), 8.25 (1H, d, J=7.8 Hz), 8.02 (1H,t, J=7.7 Hz), 7.87 (1H, t, J=7.5 Hz), 7.05 (1H, d, J=8.5 Hz), 5.35 (1H,tt, J=8.2, 3.9 Hz), 3.90-4.12 (2H, m), 3.50-3.65 (1H, m), 3.20-3.35 (1H,m), 1.93-2.16 (3H, m), 1.52-1.79 (2H, m), 0.67-0.80 (4H, m).

Example 135.1-[4-(5-Quinolin-7-yl-pyridin-2-yloxy)-piperidin-1-yl]-propan-1-one, HCl

The product was isolated as an off-white solid. Analysis: LCMS m/z=362(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.30 (1H, dd, J=5.1, 1.4 Hz), 9.14(1H, d, J=8.0 Hz), 8.72 (1H, d, J=2.3 Hz), 8.62 (1H, s), 8.44 (1H, d,J=8.8 Hz), 8.31 (1H, d, J=8.7 Hz), 8.24 (1H, dd, J=8.7, 2.6 Hz), 8.04(1H, dd, J=8.3, 5.3 Hz), 7.05 (1H, d, J=8.5 Hz), 5.29-5.37 (1H, m),3.91-4.00 (1H, m), 3.70-3.81 (1H, m), 3.30-3.42 (1H, m), 3.19-3.30 (1H,m), 2.36 (2H, q, J=7.4 Hz), 1.95-2.12 (2H, m), 1.52-1.75 (2H, m), 1.01(3H, t, J=7.4 Hz).

Example 136.2-Methyl-1-[4-(5-quinolin-7-yl-pyridin-2-yloxy)-piperidin-1-yl]-propan-1-one,HCl

The product was isolated as a tan solid. Analysis: LCMS m/z=376 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ: 9.30 (1H, dd, J=5.3, 1.3 Hz), 9.15 (1H, d,J=8.3 Hz), 8.73 (1H, d, J=2.3 Hz), 8.63 (1H, s), 8.45 (1H, d, J=8.8 Hz),8.31 (1H, dd, J=8.7, 1.6 Hz), 8.24 (1H, dd, J=8.7, 2.6 Hz), 8.05 (1H,dd, J=8.3, 5.3 Hz), 7.05 (1H, d, J=8.5 Hz), 5.31-5.38 (1H, m), 3.92-4.01(1 H, m), 3.78-3.89 (1H, m), 3.36-3.48 (1H, m), 3.19-3.31 (1H, m), 2.92(1H, quin, J=6.7 Hz), 1.95-2.15 (2H, m), 1.52-1.77 (2H, m), 1.02 (6H, d,J=6.8 Hz).

Example 137.Cyclopropyl-[4-(5-quinolin-7-yl-pyridin-2-yloxy)piperidin-1-yl]-methanone,HCl

The product was isolated as a tan solid. Analysis: LCMS m/z=374 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ: 9.29 (1H, dd, J=5.3, 1.5 Hz), 9.12 (1H, d,J=8.3 Hz), 8.73 (1H, d, J=2.3 Hz), 8.60 (1H, s), 8.44 (1H, d, J=8.8 Hz),8.23-8.32 (2H, m), 8.03 (1H, t, J=6.4 Hz), 7.05 (1H, d, J=8.8 Hz),5.32-5.40 (1H, m), 3.91-4.12 (2H, m), 3.57-3.62 (1H, m), 3.20-3.34 (1H,m), 1.95-2.16 (3H, m), 1.53-1.79 (2H, m), 0.67-0.79 (4H, m).

Example 138.2-Methyl-1-[4-(5-quinolin-3-yl-pyrimidin-2-yloxy)-piperidin-1-yl]-propan-1-one,2HCl

The product was isolated as an off-white solid. Analysis: mp: 124-130°C.; LCMS m/z=377 (M+1); ¹HNMR (DMSO-d₆) δ: 9.62 (m, 1H), 9.29 (m, 1H),9.23 (s, 2H), 8.36 (d, J=8 Hz, 2H), 8.25 (d, J=8 Hz, 1H), 8.08-8.01 (m,1H), 7.93-7.85 (m, 1H), 5.31 (m, 1H), 4.01-3.77 (m, 2H), 3.52-3.38 (m,1H), 3.36-3.23 (m, 1H), 2.92 (m, 1H), 2.17-1.97 (m, 2H), 1.81-1.56 (m,2H), 1.02 (d, J=7 Hz, 6H).

Example 139.Cyclopropyl-[4-(5-quinolin-3-yl-pyrimidin-2-yloxy)-piperidin-1-yl]-methanone,2HCl

The product was isolated as an off-white solid. Analysis: mp: 150-153°C.; LCMS m/z 375 (M+1); ¹HNMR (DMSO-d₆) δ: 9.65 (m, 1H), 9.35 (m, 1H),9.24 (s, 2H), 8.39 (m, 1H), 8.27 (m, 1H), 8.10-8.04 (m, 1H), 7.95-7.88(m, 1H), 5.33 (m, 1H), 4.15-3.85 (m, 2H), 3.71-3.51 (m, 1H), 3.39-3.23(m, 1H), 2.22-1.92 (m, 3H), 1.86-1.54 (m, 2H), 0.83-0.62 (m, 4H).

Example 140.1-[4-(6-Quinolin-3-yl-pyridin-3-yloxy)-piperidin-1-yl]-propan-1-one,2HCl

The product was isolated as an off-white solid. Analysis: mp: 207-212°C.; LCMS m/z=362 (M+1); ¹HNMR (DMSO-d₆) δ: 9.82 (m, 1H), 9.59 (m, 1H),8.54 (m, 1H), 8.41-8.30 (m, 3H), 8.11-8.03 (m, 1H), 7.95-7.88 (m, 1H),7.80-7.74 (m, 1H), 4.87 (m, 1H), 3.97-3.86 (m, 1H), 3.80-3.68 (m, 1H),3.44-3.21 (m, 2H), 2.36 (q, J=7 Hz, 2H), 2.09-1.91 (m, 2H), 1.74-1.48(m, 2H), 1.00 (t, J=7 Hz, 3H).

Example 141.2-Methyl-1-[4-(6-quinolin-3-yl-pyridin-3-yloxy)-piperidin-1-yl]-propan-1-one,2HCl

The product was isolated as an off-white solid. Analysis: mp: 99-102°C.; LCMS m/z=376 (M+1); ¹HNMR (DMSO-d₆) δ: 9.84 (m, 1H), 9.68 (m, 1H),8.55 (m, 1H), 8.44-8.33 (m, 3H), 8.15-8.07 (m, 1H), 7.99-7.91 (m, 1H),7.83-7.75 (m, 1H), 4.89 (m, 1H), 3.99-3.75 (m, 2H), 3.49-3.21 (m, 2H),2.98-2.85 (m, 1H), 2.12-1.91 (m, 2H), 1.72-1.49 (m, 2H), 1.02 (d, J=7Hz, 6H).

Example 142.Cyclopropyl-[4-(6-quinolin-3-yl-pyridin-3-yloxy)-piperidin-1-yl]-methanone,2HCl

The product was isolated as an off-white solid. Analysis: mp: 230-234°C.; LCMS m/z=374 (M+1); ¹HNMR (DMSO-d₆) δ: 9.84 (d, J=2 Hz, 1H), 9.67(m, 1H), 8.55 (d, J=3 Hz, 1H), 8.42-8.35 (m, 3H), 8.12-8.08 (m, 1H),7.96-7.92 (m, 1H), 7.81-7.78 (m, 1H), 4.90 (m, 1H), 4.12-3.85 (m, 2H),3.66-3.50 (m, 1H), 3.38-3.23 (m, 1H), 2.16-1.92 (m, 3H), 1.77-1.51 (m,2H), 0.79-0.66 (m, 4H).

Example 143.1-[4-(5-Quinolin-3-yl-pyrimidin-2-yloxy)-piperidin-1-yl]-propan-1-one

The product was isolated as a white solid. Analysis: mp: 162-166° C.;LCMS m/z=363 (M+1); ¹HNMR (DMSO-d₆) δ: 9.29 (d, J=2 Hz, 1H), 9.15 (s,2H), 8.75 (d, J=2 Hz, 1H), 8.06-8.03 (m, 2H), 7.83-7.79 (m, 1H),7.70-7.66 (m, 1H), 5.28 (m, 1H), 4.00-3.88 (m, 1H), 3.81-3.70 (m, 1H),3.44-3.20 (m, 2H), 2.37 (q, J=8 Hz, 2H), 2.14-1.95 (m, 2H), 1.80-1.55(m, 2H), 1.01 (t, J=8 Hz, 3H).

Example 144.1-[4-(6-Quinolin-7-yl-pyridin-3-yloxy)-piperidin-1-yl]-propan-1-one,2HCl

The product was isolated as an off-white solid. Analysis: mp: 90-96° C.;LCMS m/z=362 (M+1); ¹HNMR (DMSO-d₆) δ: 9.31 (m, 1H), 9.18 (m, 1H), 9.05(s, 1H), 8.63 (m, 1H), 8.57 (m, 1H), 8.45 (d, J=9 Hz, 1H), 8.22 (d, J=9Hz, 1H), 8.10-8.04 (m, 1H), 7.76-7.70 (m, 1H), 4.86 (m, 1H), 3.99-3.87(m, 1H), 3.80-3.68 (m, 1H), 3.43-3.32 (m, 1H), 3.32-3.21 (m, 1H), 2.36(q, J=7, 7 Hz, 2H), 2.11-1.92 (m, 2H), 1.73-1.51 (m, 2H), 1.00 (t, J=7Hz, 3H).

Example 145.2-Methyl-1-[4-(6-quinolin-7-yl-pyridin-3-yloxy)-piperidin-1-yl]-propan-1-one,2HCl

The product was isolated as an off-white solid. Analysis: mp: 170-179°C.; LCMS m/z=376 (M+1); ¹HNMR (DMSO-d₆) δ: 9.30 (m, 1H), 9.17 (m, 1H),9.02 (s, 1H), 8.63-8.57 (m, 2H), 8.44 (d, J=9 Hz, 1H), 8.22 (d, J=9 Hz,1H), 8.07-8.04 (m, 1H), 7.74-7.71 (m, 1H), 4.87 (m, 1H), 3.98-3.88 (m,1H), 3.88-3.76 (m, 1H), 3.49-3.36 (m, 1H), 3.34-3.20 (m, 1H), 2.92 (m,1H), 2.14-1.91 (m, 2H), 1.74-1.46 (m, 2H), 1.02 (d, J=7 Hz, 6H).

Example 146.Cyclopropyl-[4-(6-quinolin-7-yl-pyridin-3-yloxy)-piperidin-1-yl]-methanone,2HCl

The product was isolated as an off-white solid. Analysis: mp: 170-175°C.; LCMS m/z=374 (M+1); ¹HNMR (DMSO-d₆) δ: 9.31 (m, 1H), 9.19 (m, 1H),9.05 (s, 1H), 8.64-8.58 (m, 2H), 8.46 (d, J=9 Hz, 1H), 8.23 (d, J=9 Hz,1H), 8.09-8.05 (m, 1H), 7.76-7.73 (m, 1H), 4.89 (m, 1H), 4.11-3.98 (m,1H), 3.98-3.85 (m, 1H), 3.65-3.48 (m, 1H), 3.37-3.19 (m, 1H), 2.16-1.92(m, 3H), 1.77-1.50 (m, 2H), 0.77-0.66 (m, 4H).

Example 147.1-[4-(6-Isoquinolin-6-yl-pyridin-3-yloxy)-piperidin-1-yl]-propan-1-one,2HCl

The product was isolated as an off-white solid. Analysis: mp: 236-245°C.; LCMS m/z=362 (M+1); ¹HNMR (DMSO-d₆) δ: 9.92 (s, 1H), 9.00 (s, 1H),8.74-8.68 (m, 2H), 8.64-8.55 (m, 3H), 8.30 (d, J=9 Hz, 1H), 7.76-7.73(m, 1H), 4.88 (m, 1H), 3.98-3.86 (m, 1H), 3.80-3.68 (m, 1H), 3.44-3.21(m, 2H), 2.36 (q, J=8 Hz, 2H), 2.11-1.92 (m, 2H), 1.74-1.50 (m, 2H),1.00 (t, J=7 Hz, 3H).

Example 148.1-[4-(6-Isoquinolin-6-yl-pyridin-3-yloxy)-piperidin-1-yl]-2-methyl-propan-1-one,2HCl

The product was isolated as an off-white solid. Analysis: mp: 236-241°C.; LCMS m/z=376 (M+1); ¹HNMR (DMSO-d₆) δ: 9.92 (s, 1H), 9.00 (s, 1H),8.74-8.55 (m, 5H), 8.31 (d, J=9 Hz, 1H), 7.76-7.73 (m, 1H), 4.89 (m,1H), 3.98-3.88 (m, 1H), 3.88-3.76 (m, 1H), 3.49-3.37 (m, 1H), 3.33-3.22(m, 1H), 2.92 (m, 1H), 2.11-1.93 (m, 2H), 1.72-1.50 (m, 2H), 1.02 (d,J=7 Hz, 6H).

Example 149.Cyclopropyl-[4-(6-isoquinolin-6-yl-pyridin-3-yloxy)-piperidin-1-yl]-methanone,2HCl

The product was isolated as an off-white solid. Analysis: mp: 136-146°C.; LCMS m/z=374 (M+1); ¹HNMR (DMSO-d₆) δ: 9.91 (s, 1H), 9.00 (s, 1H),8.75-8.56 (m, 5H), 8.31 (d, J=9 Hz, 1H), 7.77-7.74 (m, 1H), 4.90 (m,1H), 4.11-3.98 (m, 1H), 3.98-3.86 (m, 1H), 3.66-3.50 (m, 1H), 3.38-3.22(m, 1H), 2.16-1.93 (m, 3H), 1.77-1.52 (m, 2H), 0.78-0.68 (m, 4H).

Example 150 1-Propionyl-piperidine-4-carboxylic acidmethyl-(4-quinolin-7-yl-phenyl)-amide

Step. 1-(2,2,2-Trifluoroacetyl)-piperidine-4-carboxylic acid(4-bromophenyl)-methyl-amide

1-(2,2,2-Trifluoroacetyl)-piperidine-4-carbonyl chloride (0.400 g, 1.64mmol) and DIPEA (0.858 mL, 4.92 mmol) in DCM (6 mL) was added(4-bromophenyl)-methylamine (0.413 mL, 3.29 mmol). After stirring 4 h atrt the mixture was concentrated, dissolved in EtOAc and washed with 1NNa₂CO₃, water and brine then dried over MgSO₄. The product was purifiedby silica gel chromatography (15% EtOAc/hexanes) to give a viscous oil.Analysis: LCMS m/z=394 (M+1).

Step 2. Piperidine-4-carboxylic acidmethyl-(4-quinolin-7-yl-phenyl)amide

Palladium acetate (0.00571 g, 0.0254 mmol) and triphenylphosphine(0.0267 g, 0.102 mmol) in dioxane were stirred 15 min under anatmosphere of nitrogen.1-(2,2,2-trifluoro-acetyl)-piperidine-4-carboxylic acid(4-bromo-phenyl)-methyl-amide (0.200 g, 0.509 mmol), quinoline-7-boronicacid (0.0968 g, 0.560 mmol), DMF (2 mL) and 1 M of sodium carbonate(2.03 mL, 2.03 mmol) were added, purged under an atmosphere of nitrogenand heated at 80° C. for 17 h. The mixture was concentrated, wasdissolved in EtOAc was washed with 1N Na₂CO₃, water and brine, thendried over MgSO₄. The product was purified by ISCO (silica gel, 0-25%MeOH/1% iPrNH₂,DCM) to give the compound as an oil. Analysis: LCMSm/z=346 (M+1).

Step 3. 1-Propionyl-piperidine-4-carboxylic acidmethyl-(4-quinolin-7-yl-phenyl)-amide

Piperidine-4-carboxylic acid methyl-(4-quinolin-7-yl-phenyl)amide (0.070g, 0.20 mmol) and DIPEA (0.14 mL, 0.81 mmol) in THF (3 mL) was addedpropanoyl chloride (0.035 mL, 0.40 mmol). After stirring 4 h at rt, themixture was concentrated, diluted with EtOAc and washed with 1N Na₂CO₃,water and brine then dried (MgSO₄). The product was purified by ISCOsilica gel (0-5% MOH/DCM). The HCl salt was prepared by adding 2 MHCl-ether to a DCM solution of base and crystallizing from DCM-ethergive a light yellow solid (60 mg, 73%). Analysis: LCMS m/z=402 (M+1); ¹HNMR (DMSO-d₆ HCl salt) δ: 9.20 (d, 1H, J=4 Hz), 8.91 (d, 1H, J=8 Hz),8.523 (s, 1H), 8.34 (d, 1H, J=8 Hz), 8.23 (d, 1H, J=8 Hz), 7.99 (d, 2H,J=8 Hz), 8.88-8.92 (m, 1H), 7.57 (d, 2H, J=8 Hz), 4.31 (d, 1H, J=12 Hz),3.78 (d, 1H, J=12 Hz), 3.37 (q, 1H, J=7.8 Hz), 3.22 (s, 3H), 2.8 (b,1H), 2.23-2.32 (m, 2H), 1.53-1.65 (m, 3H), 1.42 (m, 1H), 1.09 (t, 2H,J=7.3 Hz), 0.95 (t, 3H, J=7.3 Hz).

Example 151. 1-Propionyl-piperidine-4-carboxylic acid(4-isoquinolin-6-yl-phenyl)-methylamide

This example was synthesized using the procedure for example 150.Piperidine-4-carboxylic acid (4-isoquinolin-6-yl-phenyl)-methylamide(0.048 g, 0.14 mmol) and DIPEA (0.097 mL, 0.55 mmol) in THF (2 mL) wasadded propanoyl chloride (0.024 mL, 0.28 mmol). After 4 h stirring atrt, the mixture was concentrated, diluted with EtOAc and washed with 1NNa₂CO₃, water and brine then dried (MgSO₄). The product was purified byISCO silica gel 0-5% MeOH/DCM. The HCl salt was made from 2N HCl etherand crystallized from DCM-ether to give a white solid (33 mg, 59%).Analysis: LCMS m/z=402 (M+1); ¹H NMR (DMSO) δ: 9.82 s, 1H), 8.67 (m,2H), 8.57 (d, 1H, J=8 Hz), 8.37-8.42 (m, 2H), 8.06 d, 2H, J=8 Hz), 7.59(d, 2H, J=8 Hz), 4.32 (d, 1H, J=12 Hz), 3.78 (d, 2H, J=12 Hz), 3.23 (s,3H), 2.77 (b, 1H), 2.23-2.32 (m, 3H), 1.53-1.65 (m, 3H), 1.37-1.45 (m,1H), 0.95 (t, 3H, J=7 Hz).

Example 152- and Example 153 (as a Mixture)

A mixture of 3-[4-(piperidin-4-yloxy)-phenyl]-quinoline; 2HCl (100 mg,0.27 mmol), glyoxalic acid hydrate (25.6 mg, 0.28 mmol),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (HATU), 121 mg, 0.32 mmol), and DIPEA (462 μL, 2.65mmol) in THE (7 mL) was stirred at room temp for 1 h. To the reactionwas added 2-bromoethanol (150 mL, 2.10 mmol) followed by K₂CO₃ (73.3 mg,0.53 mmol). After stirred at 60° C. for 24 h, to the reaction was addedadditional 8 eq. of K₂CO₃ and continued heating for additional 3 h.After cooled to room temp, it was diluted with DCM (50 mL), washed withH₂O, dried (Na₂SO₄), and concentrated. The mixtures of two products wereseparated by pre-HPLC and each product fractions were combined,neutralized with sat. NaHCO₃ (25 mL), extracted with DCM (3×25 mL), andthe combined organic layers were dried (Na₂SO₄), and concentrated. Bothproducts were dissolved in DCM (˜5 mL) and mixed with 1.2 eq. of 2 M HClin Et₂O and concentrated. Both residues were dissolved in a small amountof DCM and concentrated—repeated this procedure several times, dried togive to give Example 152 (43 mg, 37%) and Example 153 (35 mg, 35%).

Example 152.Oxo-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-acetaldehyde, HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=405(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.49-9.55 (1H, m), 9.13-9.19 (1H,m), 8.22-8.33 (2H, m), 7.90-8.03 (3H, m), 7.82-7.89 (1H, m), 7.19-7.26(2H, m), 5.68-5.72 (1H, m), 4.75-4.84 (1H, m), 3.88-4.02 (4H, m),3.77-3.88 (2H, m), 3.41-3.52 (1H, m), 3.27-3.38 (1H, m), 1.91-2.08 (2H,m), 1.51-1.74 (2H, m).

Example 153. 4-(4-Quinolin-3-yl-phenoxy)-piperidine-1-carbaldehyde, HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=333(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.50-9.57 (1H, m), 9.15-9.23 (1H,m), 8.23-8.35 (2H, m), 7.91-8.06 (4H, m), 7.82-7.90 (1H, m), 7.19-7.28(2H, m), 4.76-4.85 (1H, m), 3.72-3.83 (1H, m), 3.58-3.69 (1H, m),3.21-3.40 (2H, m), 1.90-2.08 (2H, m), 1.50-1.71 (2H, m).

Example 154.((2R,3S)/(2S,3R)-3-Methyl-tetrahydrofuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone,HCl

Step 1. (2R,3S)/(2S,3R)-3-Methyl-tetrahydrofuran-2-carboxylic acid

A Parr bottle charged with 3-methyl-2-furoic acid (0.50 g, 4.0 mmol) and5% Rh/C (5:95, Rhodium:carbon black) (50 mg, 0.02 mmol) in methanol (25mL) was hydrogenated at 50 psi for 79 h. The reaction was filteredthrough a pad of Celite, eluted with MeOH, and the filtrate wasconcentrated to give light-brown oil crude product as racemic mixture.This material was used for next step without purification. Analysis: ¹HNMR (400 MHz, DMSO-d₆) δ: 12.18-12.80 (1H, m), 4.24 (1H, d, J=7.5 Hz),3.92-4.00 (1H, m), 3.68-3.76 (1H, m), 2.42-2.49 (1H, m), 1.99-2.09 (1H,m), 1.51-1.63 (1H, m), 0.93 (3H, d, J=7.0 Hz).

Step 2

A vial charged with 3-[4-(piperidin-4-yloxy)-phenyl]-quinoline; 2HCl(110 mg, 0.29 mmol),(2R,3S)/(2S,3R)-3-methyl-tetrahydrofuran-2-carboxylic acid (47 mg, 0.36mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (HATU, 122 mg, 0.32 mmol), and DIPEA (305 μL, 1.75mmol) in THF (10 mL) was stirred at rt 16 h. The reaction wasconcentrated and the residue was purified by pre-HPLC and the productfractions were combined, neutralized with sat. NaHCO₃ (25 mL), extractedwith DCM (3×25 mL), and the combined organic layers were dried (Na₂SO₄),and concentrated. The product was dissolved in DCM (˜5 mL) and mixedwith 1.2 eq. of 2 M HCl in Et₂O and concentrated. The residue wasdissolved in a small amount of DCM and concentrated—repeated thisprocedure several times, dried to give a yellow solid 93 mg (71%).Analysis: LCMS m/z=417 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.50-9.56(1H, m), 9.15-9.21 (1H, m), 8.23-8.34 (2H, m), 7.91-8.03 (3H, m),7.82-7.90 (1H, m), 7.18-7.27 (2H, m), 4.72-4.85 (2H, m), 3.92-4.01 (2H,m), 3.79-3.91 (1H, m), 3.66-3.77 (1H, m), 3.18-3.52 (2H, m), 2.52-2.61(1H, m), 1.91-2.10 (3H, m), 1.49-1.73 (3H, m), 0.84-0.94 (3H, m).

The following compounds were synthesized using the procedure for Example154.

Example 155.((2R,3S,5R)/(2S,3R,5S)-3,5-Dimethyl-tetrahydrofuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=431(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.50-9.54 (1H, m), 9.14-9.18 (1H,m), 8.22-8.32 (2H, m), 7.91-8.02 (3H, m), 7.82-7.89 (1H, m), 7.19-7.26(2H, m), 4.71-4.84 (2H, m), 3.89-4.04 (1H, m), 3.79-3.89 (1H, m),3.70-3.79 (1H, m), 3.30-3.53 (1H, m), 3.17-3.27 (1H, m), 2.53-2.61 (1H,m), 2.08-2.19 (1H, m), 1.91-2.08 (2H, m), 1.49-1.70 (2H, m), 1.22-1.27(4H, m), 0.86-0.93 (3H, m).

Example 156.((2R,3S,5R)/(2S,3R,5S)-3,5-Dimethyl-tetrahydrofuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone,HCl

((2R,4R,5R)/(2S,4S,5S)-4,5-Dimethyl-tetrahydrofuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone,HCL. The product was isolated as a yellow solid. Analysis: LCMS m/z=431(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.48-9.51 (1H, m), 9.10-9.14 (1H,m), 8.21-8.28 (2H, m), 7.90-8.00 (3H, m), 7.81-7.87 (1H, m), 7.19-7.25(2H, m), 4.74-4.82 (1H, m), 4.53-4.59 (1H, m), 3.98-4.05 (1H, m),3.79-3.91 (2H, m), 3.38-3.51 (1H, m), 3.25-3.37 (1H, m), 2.21-2.29 (1H,m), 2.09-2.18 (1H, m), 1.86-2.05 (3H, m), 1.51-1.69 (2H, m), 0.98-1.02(3H, m), 0.87-0.90 (3H, m).

Example 157. 1-Propionylpiperidine-4-carboxylic acid(4-isoquinolin-6-yl-phenyl)-methylamide

Step 1.4-[(4-Bromo-2-fluorobenzoyl)-methylamino]-piperidine-1-carboxylic acidtert-butyl ester

4-Methylamino-piperidine-1-carboxylic acid tert-butyl ester (0.40 g,1.87 mmol) and DIPEA (1.30 mL, 7.47 mmol) in DCM (5 mL) was added4-bromo-2-fluoro-benzoyl chloride (0.488 g, 2.05 mmol). After 2 hstirring at rt the mixture was concentrated, dissolved in EtOAc andwashed with 1N Na₂CO₃, water and brine. The product was purified bysilica gel chromatography (20% EtOAc/hexanes) to give an oil (0.6 g,77%). Analysis: LCMS m/z=416 (M+1).

Step 2. 2-Fluoro-4-isoquinolin-6-yl-N-methyl-N-piperidin-4-yl-benzamide

Palladium acetate (0.007568 g, 0.03371 mmol) and triphenylphosphine(0.03537 g, 0.1348 mmol) in dioxane were stirred 15 min under anatmosphere of nitrogen.4-[(4-bromo-2-fluoro-benzoyl)-methyl-amino]-piperidine-1-carboxylic acidtert-butyl ester (0.3500 g, 0.8428 mmol), isoquinoline-6-boronic acid(0.2187 g, 1.264 mmol), DMF (6 mL) and 1 M of sodium carbonate (2.56 mL)was added and heated at 80° C. for 17 h. The mixture was concentrated,was dissolved in EtOAc, washed with 1N Na₂CO₃, water and brine thendried (MgSO₄). The product was purified by ISCO (silica get, 12 g, 0-5%MeOH/DCM) to give a white solid. This material was dissolved in 4 M HClin 1,4-dioxane (6 mL, 20 mmol) and was heated at 65° C. for 4 h. Thematerial was concentrated, partitioned between EOAc and 1N Na₂CO₃,washed with water and brine then dried over MgSO₄ to give an oil. Theamine was purified by ISCO (4 g silica gel, 0-10% MeOH with 1% IPA/DCM)to give an oil (0.25 g, 81%). Analysis: LCMS m/z=364 (M+1).

Step 3. 1-Propionylpiperidine-4-carboxylic acid(4-isoquinolin-6-yl-phenyl)-methylamide

Piperidine-4-carboxylic acid (4-isoquinolin-6-yl-phenyl)-methylamide(0.048 g, 0.14 mmol) and DIPEA (0.097 mL, 0.55 mmol) in THF (2 mL) wasadded propanoyl chloride (0.024 mL, 0.28 mmol). After 4 h stirring atrt, the mixture was concentrated, diluted with EtOAc and washed with 1NNa₂CO₃, water and brine then dried (MgSO₄). The product was purified byISCO silica gel 0-5% MeOH/DCM. The HCl salt was prepared from 2N HClether and crystallized from DCM-ether to give a white solid (33 mg,59%). Analysis: LCMS m/z=402 (M+1); ¹H NMR (DMSO; HCl salt) δ: 9.82 (s,1H), 8.67 (m, 2H), 8.57 (d, 1H, J=8 Hz), 8.37-8.42 (m, 2H), 8.06 d, 2H,J=8 Hz), 7.59 (d, 2H, J=8 Hz), 4.32 (d, 1H, J=12 Hz), 3.78 (d, 2H, J=12Hz), 3.23 (s, 3H), 2.77 (b, 1H), 2.23-2.32 (m, 3H), 1.53-1.65 (m, 3H),1.37-1.45 (m, 1H), 0.95 (t, 3H, J=7 Hz).

Example 158.2-Fluoro-4-isoquinolin-6-yl-N-methyl-N-(1-propionyl-piperidin-4-yl)-benzamide

This example was synthesized using the procedure for example 157.Analysis: LCMS m/z=420 (M+1); ¹H NMR (DMSO; HCl salt) δ: 9.84 (s, 1H),8.70 (m, 2H), 8.58 (d, 2H, J=8.5 Hz), 8.38-8.42 (m, 2H), 7.96 (t, 1H,J=10 Hz), 7.88 (m, 1H), 7.95-7.69 (m, 1H), (rotomers 2:1) 4.58/4.44 (m,2H), 3.98/3.86 (bd, 1H), 3.54/3.12 (1:1, m, 1H), 2.91/2.75 (1:2, s, 3H),2.80/2.62 (1:1, m, 1H), 2.77-2.83 (m, 3H), 1.61-1.80 (m, 4H), 0.93-1.02(m, 3H).

Example 159.1-{4-[4-(3-Trifluoromethyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,HCl

Step 1.4-[4-(3-Trifluoromethyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester

A flask charged with 4-(4-iodo-phenoxy)-piperidine-1-carboxylic acidtert-butyl (368 mg, 0.91 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-trifluoromethyl-1,2,4-triazolo[4,3-a]pyridine(0.30 g, 0.96 mmol), palladium acetate (20.5 mg, 0.91 mmol),triphenylphosphine (47.9 mg, 0.18 mmol), 1.0 M of Na₂CO₃ in water (5 mL,5 mmol), 1,4-dioxane (5 mL), and DMF (5 mL) was flashed with N₂ for 15min. The reaction was stirred at 90° C. for 16 h then cooled to rt andconcentrated. The residue was participated in EtOAc (80 mL) and sat.NaHCO₃ solution (30 mL), the organic layer was separated and the waterlayer was extracted with EtOAc (50 mL). The combined organic layers werewashed with H₂O, brine, dried (Na₂SO₄), and concentrated. The residuewas chromatography on silica gel (10-70% EtOAc/Hexanes) to give anoff-white solid (404 mg, 96%). Analysis: ¹H NMR (400 MHz, DMSO-d₆) δ:8.59-8.61 (1H, m), 8.09-8.14 (1H, m), 7.95-8.00 (1H, m), 7.71-7.76 (2H,m), 7.11-7.16 (2H, m), 4.63-4.72 (1H, m), 3.63-3.72 (2H, m), 3.16-3.28(2H, m), 1.90-1.98 (2H, m), 1.50-1.61 (2H, m), 1.41 (9H, s).

Step 2.6-[4-(Piperidin-4-yloxy)-phenyl]-3-trifluoromethyl-1,2,4-triazolo[4,3-a]pyridine,2HCl

To a solution of4-[4-(3-trifluoromethyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)-phenoxy]piperidine-1-carboxylicacid tert-butyl ester (396 mg, 0.86 mmol) in DCM (15 mL) was added 4.0 Mof hydrogen chloride in 1,4-dioxane (2.14 mL, 8.56 mmol) and stirred atRT for 18 h. The resulted white precipitation was collected byfiltration, washed with DCM, dried to give a white solid 370 mg (99%).Analysis: LCMS m/z=363 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.15 (1H, br.s.), 8.59-8.63 (1H, m), 8.10-8.16 (1H, m), 7.96-8.02 (1H, m), 7.74-7.79(2H, m), 7.14-7.20 (2H, m), 4.73-4.82 (1H, m), 3.18-3.30 (2H, m),3.03-3.15 (2H, m), 2.10-2.21 (2H, m), 1.83-1.95 (2H, m).

Step 3

To a solution of6-[4-(piperidin-4-yloxy)-phenyl]-3-trifluoromethyl-1,2,4-triazolo[4,3-a]pyridine;2HCl (85 mg, 0.20 mmol), DIPEA (170 μL, 0.98 mmol) in THF (6 mL) wasadded propanoyl chloride (19 μL, 0.22 mmol). After 25 min, the reactionwas concentrated and the residue was chromatography on silica gel (0-10%MeOH/DCM) and the isolated product was dissolved in DCM (˜5 mL) andmixed with 1.2 eq. of 2 M HCl in Et₂O and concentrated. The residue wasdissolved in a small amount of DCM and concentrated—repeated thisprocedure several times, dried to give to give a light-brown solid 63 mg(71%). Analysis: LCMS m/z=419 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ:8.58-8.63 (1H, m), 8.09-8.15 (1H, m), 7.96-8.01 (1H, m), 7.71-7.78 (2H,m), 7.12-7.18 (2H, m), 4.68-4.78 (1H, m), 3.82-3.93 (1H, m), 3.66-3.76(1H, m), 3.22-3.41 (2H, m), 2.35 (2H, q, J=7.5 Hz), 1.87-2.04 (2H, m),1.47-1.69 (2H, m), 1.00 (3H, t, J=7.4 Hz).

The following compounds were synthesized using the procedure for Example159.

Example 160.Cyclopropyl-{4-[4-(3-trifluoromethyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone,HCl

The product was isolated as an off-white solid. Analysis: LCMS m/z=431(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.59-8.63 (1H, m), 8.10-8.15 (1H,m), 7.96-8.01 (1H, m), 7.72-7.78 (2H, m), 7.13-7.18 (2H, m), 4.71-4.79(1H, m), 3.83-4.04 (2H, m), 3.50-3.63 (1H, m), 3.24-3.35 (1H, m),1.88-2.09 (3H, m), 1.48-1.71 (2H, m), 0.67-0.75 (4H, m).

Example 161.(R)-Tetrahydrofuran-2-yl-{4-[4-(3-trifluoromethyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone

To a solution of6-[4-(piperidin-4-yloxy)-phenyl]-3-trifluoromethyl-1,2,4-triazolo-[4,3-a]pyridine; 2HCl (85 mg, 0.20 mmol), HATU (81.7 mg. 0.22 mmol), DIPEA(170 mL, 0.98 mmol) in THF (6 mL) was added(R)-tetrahydrofuran-2-carboxylic acid (20 μL, 0.21 mmol) and stirred atrt for 1 h. The reaction was concentrated and the residue was purifiedby chromatography on silica gel (0-10% MeOH/DCM) to give a white solid71 mg (79%). Analysis: LCMS m/z=461 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ:8.59-8.62 (1H, m), 8.10-8.15 (1H, m), 7.96-8.01 (1H, m), 7.72-7.77 (2H,m), 7.12-7.18 (2H, m), 4.66-4.78 (2H, m), 3.70-3.87 (4H, m), 2.68-2.70(2H, m), 1.92-2.10 (4H, m), 1.79-1.88 (2H, m), 1.49-1.69 (2H, m).

Example 162.3-[4-(1-Methanesulfonyl-piperidin-4-yloxy)-phenyl]-quinoline

Step 1. Methanesulfonic acid (R)-1-(tetrahydrofuran-2-yl)methyl ester

To a solution of (R)-1-(tetrahydrofuran-2-yl)-methanol (0.50 g, 4.9mmol), and DIPEA (2.56 mL, 14.7 mmol) in methylene chloride (20 mL) at0° C. was added methanesulfonyl chloride (398 μL, 5.14 mmol). After 1 hat 0° C., the reaction was stirred at room temp over night (16 h) thenquenched with H₂O (20 mL), extracted with DCM (3×30 mL). The combinedorganic layers were washed with H₂O, dried (Na₂SO₄) and concentrated togive 551 mg (62%) of crude product. This material was used for next stepwithout purification.

Step 2

A vial charged with 3-[4-(piperidin-4-yloxy)-phenyl]-quinoline; 2HCl (85mg, 0.22 mmol), methanesulfonic acid (R)-1-(tetrahydrofuran-2-yl)methylester (61 mg, 0.34 mmol), potassium carbonate (160 mg, 1.1 mmol), andacetonitrile (6 mL) was stirred at 90° C. for 1.5 h. After cooled to RT,it was diluted with DCM (50 mL), washed with H₂O, dried (Na₂SO₄), andconcentrated. The residue was chromatography on silica gel (0-10%MeOH/DCM) to give a white solid 76 mg (88%). Analysis: LCMS m/z=373(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.22-9.25 (1H, m), 8.57-8.59 (1H,m), 8.01-8.06 (2H, m), 7.82-7.87 (2H, m), 7.72-7.78 (1H, m), 7.61-7.67(1H, m), 7.15-7.20 (2H, m), 4.64-4.72 (1H, m), 3.34-3.43 (2H, m),3.14-3.20 (2H, m), 2.92 (3H, s), 2.01-2.10 (2H, m), 1.74-1.85 (2H, m).

Example 163.(4,4-Difluorotetrahydrofuran-2-yl)-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone,HCl

Step 1. 4-oxo-tetrahydrofuran-2-carboxylic acid

To a suspension of sodium hydride, 60% disp. in mineral oil (830 mg,20.7 mmol) in THF (35 mL) was added a solution of ethyl glycolate (2.0mL, 20.7 mmol) in THF (5 mL×2) dropwise at rt (water-bath). After theevolution of H₂ had ceased (˜5 min), to the reaction was added(Z)-2-butenedioic acid, diethyl ester (2.75 mL, 17.0 mmol). The reactionwas stirred at 65° C. for 1 h then rt for 5 days. The solvent wasremoved and to the residue was carefully added ice-water (50 mL) and 1NHCl solution (50 mL), extracted with EtOAc (2×50 mL), the combinedorganic layers were concentrated. This residue was heated at reflux(100° C.) with 10% H₂OS₄ water solution for 5 h and cooled to rt. Thereaction was extracted with EtOAc (3×50 mL) and the combined organiclayers were washed with brine, dried (Na₂SO₄), and concentrated. Thismaterial was use for next step without purification.

Step 2. 4-oxo-Tetrahydrofuran-2-carboxylic acid 4-nitro-benzyl ester

To a mixture of 4-oxo-tetrahydrofuran-2-carboxylic acid (2.21 g, 17.0mmol), DIPEA (2.95 mL, 16.9 mmol), 4-dimethylaminopyridine (156 mg, 1.27mmol), potassium carbonate (3.52 g, 25.5 mmol) in THF (35 mL) was addeda solution of 4-nitrobenzyl chloroformate (2.75 g, 12.7 mmol) in THF (5mL) at rt (water-bath). After 5 min, the solvent was removed and theresidue was added H₂O (30 mL), extracted with EtOAc (2×50 mL). Thecombined organic layers were washed with brine, dried (Na₂SO₄), andconcentrated. The residue was chromatography on silica gel (0-50%EtOAc/Hexanes) to give a white solid (934 mg, 28%, 3 steps). Analysis:¹H NMR (400 MHz, CDCl₃) δ: 8.22-8.28 (2H, m), 7.50-7.57 (2H, m),5.29-5.33 (2H, m), 4.96-5.03 (1H, m), 4.15-4.23 (1H, m), 4.00-4.07 (1H,m), 2.81-2.91 (1H, m), 2.60-2.69 (1H, m).

Step 3. 4,4-Difluorotetrahydrofuran-2-carboxylic acid 4-nitrobenzylester

A Teflon bottle charged with 4-oxo-tetrahydrofuran-2-carboxylic acid4-nitro-benzyl ester (538 mg, 2.03 mmol) in DCM (10 mL) was addedbis(2-methoxyethyl)aminosulfur trifluoride (1.12 mL, 6.08 mmol) andstirred at rt for 18 h. The reaction was carefully added sat. NH₄Clsolution (15 mL) cooling with water-bath, extracted with DCM (3×10 mL).The combined organic layers was dried (Na₂SO₄) and concentrated. Theresidue was chromatography on silica gel (0-30% EtOAc/Hexanes) to givecolorless oil (496 mg, 85%). Analysis: ¹H NMR (400 MHz, CDCl₃) δ:8.22-8.27 (2H, m), 7.51-7.56 (2H, m), 5.31 (2H, s), 4.75-4.81 (1H, m),4.00-4.24 (2H, m), 2.70-2.84 (1H, m), 2.54-2.68 (1H, m).

Step 4. 4,4-Difluorotetrahydrofuran-2-carboxylic acid

To a solution of 4,4-difluorotetrahydrofuran-2-carboxylic acid4-nitro-benzyl ester (270 mg, 0.94 mmol) in THF (6 mL) was added 1.0 Mof tetra-n-butylammonium fluoride in THF (2.35 mL, 2.35 mmol) andstirred for 30 min. The reaction was added H₂O (10 mL) and EtOAc (10 mL)then extracted with 5% NaHCO₃ solution (3×15 mL). The combined waterlayers were acidified to pH-1 with HCl, extracted with EtOAc (3×20 mL).The combined organic layers were washed with brine, dried (Na₂SO₄), andconcentrated to give a brown oil 140 mg. This material was used for nextstep without purification.

Step 5

A mixture of 3-[4-(piperidin-4-yloxy)-phenyl]-quinoline; 2HCl (106 mg,0.28 mmol), 4,4-difluorotetrahydrofuran-2-carboxylic acid (51 mg, 0.34mmol), HATU (107 mg, 0.28 mmol), DIPEA (245 μL, 1.40 mmol) in THF (8 mL)was stirred at rt for 1 h and concentrated. The residue was purified bypre-HPLC and the product fractions were combined and concentrated. Theresidue was added EtOAc (25 mL), washed with sat. NaHCO₃ solution (10mL), brine, dried (Na₂SO₄), and concentrated. The product was dissolvedin DCM (˜5 mL) and mixed with 1.2 eq. of 2 M HCl in Et₂O andconcentrated. The residue was dissolved in a small amount of DCM andconcentrated—repeated this procedure several times, dried to give ayellow solid 117 mg (88%). Analysis: LCMS m/z=439 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ: 9.50-9.55 (1H, m), 9.14-9.19 (1H, m), 8.23-8.32 (2H,m), 7.96-8.02 (1H, m), 7.91-7.96 (2H, m), 7.83-7.89 (1H, m), 7.19-7.25(2H, m), 5.08-5.16 (1H, m), 4.75-4.84 (1H, m), 3.88-4.09 (3H, m),3.75-3.85 (1H, m), 3.27-3.53 (2H, m), 2.71-2.88 (1H, m), 2.54-2.71 (1H,m), 1.99 (2H, s), 1.54-1.70 (2H, m).

The following compounds were synthesized using the procedure for Example163.

Example 164.(4,4-Difluorotetrahydrofuran-2-yl)-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone,HCl

The product was isolated as a brown solid. Analysis: LCMS m/z=453 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ: 9.10-9.15 (1H, m), 8.76-8.87 (1H, m),8.03-8.11 (1H, m), 7.79-7.89 (1H, m), 7.64-7.71 (1H, m), 7.37-7.45 (2H,m), 7.11-7.19 (2H, m), 5.08-5.17 (1H, m), 4.69-4.79 (1H, m), 3.99-4.05(2H, m), 3.73-3.90 (2H, m), 3.25-3.53 (2H, m), 2.75-2.89 (1H, m), 2.72(3H, s), 2.54-2.70 (1H, m), 1.99 (2H, s), 1.55-1.73 (2H, m).

Example 165.(4,4-Difluorotetrahydrofuran-2-yl)-{4-[4-(1-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone,HCl

The product was isolated as an off-white solid. Analysis: LCMS m/z=453(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.55-8.63 (2H, m), 8.45-8.49 (1H,m), 8.32-8.37 (1H, m), 8.26-8.30 (1H, m), 7.92-7.98 (2H, m), 7.19-7.25(2H, m), 5.09-5.16 (1H, m), 4.76-4.85 (1H, m), 3.97-4.07 (2H, m),3.73-3.96 (2H, m), 3.41-3.50 (2H, m), 3.21 (3H, s), 2.71-2.88 (1H, m),2.55-2.70 (1H, m), 1.94-2.05 (2H, m), 1.52-1.75 (2H, m).

Example 166.5-[4-(4-Quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]dihydrofuran-3-one

A mixture of 3-[4-(piperidin-4-yloxy)-phenyl]-quinoline; 2HCl (105 mg,0.278 mmol), 4-oxo-tetrahydrofuran-2-carboxylic acid (38 mg, 0.29 mmol),HATU (116 mg, 0.31 mmol), DIPEA (242 μL, 1.39 mmol) in THF (8 mL) wasstirred at rt for 1 h and concentrated. The residue was purified bypre-HPLC and the product fractions were combined and concentrated. Theresidue was added EtOAc (25 mL), washed with sat. NaHCO₃ solution (10mL), brine, dried (Na₂SO₄), concentrated to give a white solid 17 mg(15%). Analysis: LCMS m/z=417 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ:8.57-8.60 (1H, m), 8.01-8.06 (2H, m), 7.82-7.86 (2H, m), 7.72-7.78 (1H,m), 7.61-7.66 (1H, m), 7.16-7.20 (2H, m), 5.33-5.39 (1H, m), 4.72-4.81(1H, m), 3.98 (2H, s), 3.77-3.94 (2H, m), 3.38-3.58 (2H, m), 3.26-3.31(1H, m), 2.66-2.72 (2H, m), 1.91-2.12 (2H, m), 1.51-1.79 (2H, m).

Example 167.1-{4-[4-(8-Ethoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,HCl

Step 1. 7-Bromo-8-ethoxyquinoline

A flask charged with 7-bromoquinolin-8-ol (1.0 g, 4.46 mmol), iodoethane(375 μL, 4.69 mmol), and K₂CO₃ (1.23 g, 8.93 mmol) in dimethyl sulfoxide(25 mL) was stirred at rt for 24 h. The reaction was diluted with DCM,washed with H₂O (2×30 mL), brine, dried (Na₂SO₄), and concentrated. Theresidue was chromatography on silica gel (0-50% EtOAc/Hexanes) to give1.03 g (92%) as yellowish oil.

Step 2. 4-[4-(8-ethoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester

A flask charged with4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (1.62 g, 4.01 mmol), 7-bromo-8-ethoxyquinoline(1.01 g, 4.01 mmol), palladium acetate (91 mg, 0.40 mmol),triphenylphosphine (0.21 g, 0.80 mmol), 1.0 M of Na₂CO₃ in water (20 mL,20 mmol), 1,4-dioxane (20 mL), and DMF (20 mL) was flashed with N₂ for15 min. After stirred at 85° C. for 17 h, the reaction was cooled to rt,and added EtOAc (100 mL), washed with sat. NaHCO₃ solution (35 mL), thewater layer was back extracted with EtOAc (50 mL). The combined organiclayers were washed with H₂O (35 mL), brine, dried (Na₂SO₄), andconcentrated. The residue was chromatography on silica gel (0-70%EtOAc/Hexanes) to give 1.21 g (67%) as yellowish gum. Analysis: ¹H NMR(400 MHz, DMSO-d₆) δ: 8.91-8.95 (1H, m), 8.35-8.40 (1H, m), 7.73-7.78(1H, m), 7.56-7.62 (3H, m), 7.51-7.56 (1H, m), 7.07-7.13 (2H, m),4.59-4.69 (1H, m), 4.14-4.24 (2H, m), 3.66-3.76 (2H, m), 3.13-3.28 (2H,m), 1.91-2.02 (2H, m), 1.50-1.63 (2H, m), 1.42 (9H, s), 1.14-1.21 (3H,m).

Step 3. 8-Ethoxy-7-[4-(piperidin-4-yloxy)-phenyl]-quinoline, 2HCl

To a solution of4-[4-(8-ethoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester (1.20 g, 2.68 mmol) in DCM (30 mL) was added 4.0 M ofHCl in 1,4-dioxane (6.69 mL, 26.8 mmol) slowly. The reaction was stirredat rt for 2 h and then concentrated. The solid residue was washed withmixed solvent (DCM-EtOAc ˜1:1) and dried to give 976 mg (87%) as yellowsolid.

Step 4

To a solution of 8-ethoxy-7-[4-(piperidin-4-yloxy)-phenyl]-quinoline;2HCl (150 mg, 0.36 mmol) and DIPEA (310 μL, 1.78 mmol) in THF (10 mL)was added propanoyl chloride (34 μL, 0.39 mmol) and stirred for 25 min.The solvent was removed and the residue was purified by pre-HPLC. Theproduct fractions were combined and neutralized with sat. NaHCO₃solution (25 mL), extracted with DCM (3×25 mL), dried (Na₂SO₄), andconcentrated. The product was dissolved in DCM (˜5 mL) and mixed with1.2 eq. of 2 M HCl in Et₂O and concentrated. The residue was dissolvedin a small amount of DCM and concentrated—repeated this procedureseveral times, dried to give 97 mg (62%) yellow solid. Analysis: LCMSm/z=405 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.13-9.20 (1H, m), 8.94-9.05(1H, m), 8.04-8.11 (1H, m), 7.86-8.01 (2H, m), 7.67-7.75 (2H, m),7.14-7.22 (2H, m), 4.68-4.78 (1H, m), 3.93 (3H, q, J=6.8 Hz), 3.67-3.79(1H, m), 3.20-3.43 (2H, m), 2.36 (2H, q, J=7.4 Hz), 1.90-2.09 (2H, m),1.48-1.71 (2H, m), 1.21 (3H, t, J=7.0 Hz), 1.00 (3H, t, J=7.4 Hz).

The following compounds were synthesized using the procedure for Example167.

Example 168.Cyclopropyl-{4-[4-(8-ethoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=417(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.14-9.20 (1H, m), 8.97-9.06 (1H,m), 8.05-8.12 (1H, m), 7.86-8.02 (2H, m), 7.68-7.75 (2H, m), 7.16-7.22(2H, m), 4.71-4.81 (1H, m), 3.87-3.97 (3H, m), 3.50-3.62 (1H, m),3.22-3.35 (1H, m), 1.99 (4H, s), 1.49-1.73 (2H, m), 1.22 (3H, t, J=7.0Hz), 0.62-0.85 (4H, m).

Example 169.1-{4-[4-(8-Isopropoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=419(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.16-9.21 (1H, m), 9.01-9.11 (1H,m), 8.06-8.14 (1H, m), 7.96-8.04 (1H, m), 7.89-7.95 (1H, m), 7.68-7.75(2H, m), 7.15-7.22 (2H, m), 4.68-4.78 (1H, m), 4.14-4.27 (1H, m),3.90-3.97 (1H, m), 3.71-3.77 (1H, m), 3.21-3.41 (2H, m), 2.36 (2H, q,J=7.3 Hz), 1.91-2.07 (2H, m), 1.48-1.70 (2H, m), 1.11 (6H, d, J=6.0 Hz),1.00 (3H, t, J=7.4 Hz).

Example 170.Cyclopropyl-{4-[4-(8-isopropoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=431(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.16-9.22 (1H, m), 9.03-9.12 (1H,m), 8.07-8.14 (1H, m), 7.97-8.05 (1H, m), 7.90-7.96 (1H, m), 7.69-7.76(2H, m), 7.16-7.23 (2H, m), 4.71-4.81 (1H, m), 4.15-4.27 (1H, m),4.00-4.05 (1H, m), 3.90-3.97 (1H, m), 3.53-3.60 (1H, m), 3.23-3.32 (1H,m), 1.92-2.11 (3H, m), 1.50-1.71 (2H, m), 1.12 (6H, d, J=6.0 Hz),0.67-0.78 (4H, m).

Example 171.1-(4-{4-[8-(2-Morpholin-4-yl-ethoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one,2HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=490(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.06-9.17 (1H, m), 8.70-8.87 (1H,m), 7.96-8.06 (1H, m), 7.72-7.91 (2H, m), 7.61-7.71 (2H, m), 7.11-7.20(2H, m), 4.69-4.76 (1H, m), 4.24-4.37 (2H, m), 3.87-3.99 (5H, m),3.69-3.77 (1H, m), 3.51-3.56 (2H, m), 3.22-3.43 (4H, m), 2.36 (2H, q,J=7.5 Hz), 1.89-2.08 (2H, m), 1.48-1.72 (2H, m), 1.15-1.32 (2H, m), 1.01(3H, t, J=7.4 Hz).

Example 172.Cyclopropyl-(4-{4-[8-(2-morpholin-4-yl-ethoxy)-quinolin-7-yl]-phenoxyl}-piperidin-1-yl)-methanone,2HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=502(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.08-9.14 (1H, m), 8.68-8.84 (1H,m), 7.96-8.04 (1H, m), 7.74-7.88 (2H, m), 7.67 (2H, d, J=8.8 Hz), 7.17(2H, d, J=8.8 Hz), 4.72-4.78 (1H, m), 4.26-4.36 (2H, m), 3.89-4.05 (6H,m), 3.49-3.64 (4H, m), 3.22-3.48 (4H, m), 1.91-2.14 (3H, m), 1.49-1.76(2H, m), 0.68-0.79 (4H, m).

Example 173.1-(4-{4-[8-(2-Pyrrolidin-1-yl-ethoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=474(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.16-9.25 (1H, m), 8.95-9.10 (1H,m), 8.08-8.18 (1H, m), 7.95-8.05 (1H, m), 7.86-7.94 (1H, m), 7.71 (2H,d, J=8.5 Hz), 7.20 (2H, d, J=8.8 Hz), 4.70-4.79 (1H, m), 4.08-4.19 (2H,m), 3.86-3.97 (1H, m), 3.53-3.79 (5H, m), 3.23-3.43 (2H, m), 3.00-3.16(2H, m), 2.36 (2H, q, J=7.3 Hz), 1.90-2.09 (6H, m), 1.48-1.72 (2H, m),1.01 (3H, t, J=7.4 Hz).

Example 174.Cyclopropyl-(4-{4-[8-(2-pyrrolidin-1-yl-ethoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=486(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.08-9.17 (1H, m), 8.72-8.92 (1H,m), 7.98-8.09 (1H, m), 7.77-7.94 (2H, m), 7.69 (2H, d, J=8.5 Hz), 7.18(2H, d, J=8.5 Hz), 4.71-4.80 (1H, m), 4.16-4.26 (2H, m), 3.87-4.08 (2H,m), 3.49-3.72 (5H, m), 3.23-3.37 (1H, m), 3.00-3.20 (2H, m), 1.92-2.10(7H, m), 1.49-1.75 (2H, m), 0.66-0.79 (4H, m).

Example 175.1-(4-{4-[8-(3-Pyrrolidin-1-yl-propoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=488(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.07-9.13 (1H, m), 8.71-8.82 (1H,m), 7.95-8.02 (1H, m), 7.74-7.85 (2H, m), 7.67 (2H, d, J=7.9 Hz), 7.18(2H, d, J=8.8 Hz), 4.68-4.77 (1H, m), 3.89-3.99 (3H, m), 3.69-3.79 (1H,m), 3.58-3.69 (2H, m), 3.32-3.42 (1H, m), 3.20-3.31 (3H, m), 2.93-3.06(2H, m), 2.36 (2H, q, J=7.4 Hz), 2.00-2.12 (5H, m), 1.86-1.98 (3H, m),1.49-1.70 (2H, m), 1.01 (3H, t, J=7.4 Hz).

Example 176.Cyclopropyl-(4-{4-[8-(3-pyrrolidin-1-yl-propoxy)-quinolin-7-yl]-phenoxy})-piperidin-1-yl)-methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=500(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.08-9.15 (1H, m), 8.72-8.83 (1H,m), 7.96-8.03 (1H, m), 7.75-7.88 (2H, m), 7.68 (2H, d, J=8.8 Hz), 7.19(2H, d, J=8.8 Hz), 4.71-4.80 (1H, m), 4.01-4.07 (1H, m), 3.88-3.99 (3H,m), 3.52-3.68 (3H, m), 3.19-3.33 (3H, m), 2.93-3.07 (2H, m), 2.00-2.13(6H, m), 1.87-1.98 (3H, m), 1.51-1.74 (2H, m), 0.67-0.79 (4H, m).

Example 177.1-[4-[4-[8-[2-(4-Methylpiperazin-1-yl)ethoxy]-7-quinolyl]phenoxy]-1-piperidyl]propan-1-one,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=503(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.10 (1H, d, J=3.3 Hz), 8.60-8.78(1H, m), 7.97 (1H, d, J=8.5 Hz), 7.71-7.83 (2H, m), 7.67 (2H, d, J=8.5Hz), 7.16 (2H, d, J=8.8 Hz), 4.73 (1H, dt, J=7.8, 4.0 Hz), 4.31 (2H, br.s.), 3.87-4.05 (3H, m), 3.67-3.80 (3H, m), 3.43-3.67 (6H, m), 3.22-3.42(2H, m), 2.87 (3H, s), 2.36 (2H, q, J=7.3 Hz), 1.93-2.04 (2H, m),1.49-1.71 (2H, m), 1.01 (3H, t, J=7.4 Hz).

Example 178.1-[4-[4-[8-(2-Methoxyethoxy)-7-quinolyl]phenoxy]-1-piperidyl]propan-1-one,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=435(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.13-9.19 (1H, m), 8.93-9.02 (1H,m), 8.03-8.08 (1H, m), 7.91-7.98 (1H, m), 7.85-7.90 (1H, m), 7.69 (2H,d, J=7.9 Hz), 7.17 (2H, d, J=9.0 Hz), 4.73 (1H, dt, J=7.8, 4.1 Hz),4.02-4.08 (2H, m), 3.87-3.97 (1H, m), 3.69-3.78 (1H, m), 3.54-3.59 (2H,m), 3.21-3.41 (2H, m), 3.05 (3H, s), 2.36 (2H, q, J=7.5 Hz), 1.91-2.07(2H, m), 1.48-1.70 (2H, m), 1.00 (3H, t, J=7.4 Hz).

Example 179.1-[4-[4-[8-(3-Methoxypropoxy)-7-quinolyl]phenoxy]-1-piperidyl]propan-1-one,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=449(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.15 (1H, d, J=3.8 Hz), 8.93 (1H,br. s.), 8.04 (1H, d, J=8.5 Hz), 7.89-7.96 (1H, m), 7.85 (1H, d, J=8.8Hz), 7.66 (2H, d, J=8.8 Hz), 7.17 (2H, d, J=8.8 Hz), 4.69-4.78 (1H, m),3.87-3.98 (3H, m), 3.69-3.78 (1H, m), 3.28-3.42 (1H, m), 3.25 (3H, t,J=6.4 Hz), 3.10 (3H, s), 2.36 (2H, q, J=7.5 Hz), 1.92-2.06 (2H, m), 1.88(2H, quin, J=6.5 Hz), 1.49-1.70 (2H, m), 1.00 (3H, t, J=7.4 Hz).

Example 180.{4-[4-(8-Isopropoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone,HCl

A mixture of 8-isopropoxy-7-[4-(piperidin-4-yloxy)-phenyl]-quinoline;2HCl (151 mg, 0.35 mmol), (R)-tetrahydrofuran-2-carboxylic acid (35 μL,0.36 mmol), HATU (145 mg, 0.38 mmol), and DIPEA (300 μL, 1.73 mmol) inTHF (10 mL) was stirred at rt for 1 h. The solvent was removed and theresidue was purified by pre-HPLC. The product fractions were combinedand concentrated to give yellowish oil. This oil was diluted in EtOAc(25 mL), washed with sat. NaHCO₃ solution (10 mL), brine, dried(Na₂SO₄), and concentrated. The product was dissolved in DCM (˜5 mL) andmixed with 1.2 eq. of 2 M HCl in Et₂O and concentrated. The residue wasdissolved in a small amount of DCM and concentrated—repeated thisprocedure several times, dried to give 129 mg (75%) of yellow solid.Analysis: LCMS m/z=461 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.15-9.20(1H, m), 8.99-9.09 (1H, m), 8.05-8.12 (1H, m), 7.95-8.03 (1H, m),7.88-7.95 (1H, m), 7.69-7.75 (2H, m), 7.15-7.22 (2H, m), 4.67-4.80 (2H,m), 4.17-4.27 (1H, m), 3.72-3.87 (5H, m), 3.24-3.48 (2H, m), 2.00-2.09(3H, m), 1.77-1.89 (2H, m), 1.48-1.71 (2H, m), 1.11 (6H, d, J=6.0 Hz).

The following compounds were synthesized using the procedure for Example180.

Example 181.{4-[4-(8-Ethoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone,HCl

The product was isolated as a brown solid. Analysis: LCMS m/z=447 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ: 9.11-9.19 (1H, m), 8.91-9.04 (1H, m),8.03-8.11 (1H, m), 7.85-7.99 (2H, m), 7.67-7.75 (2H, m), 7.13-7.22 (2H,m), 4.65-4.82 (2H, m), 4.03 (1H, q, J=7.1 Hz), 3.92-3.97 (2H, m),3.82-3.89 (1H, m), 3.73-3.81 (2H, m), 3.18-3.52 (2H, m), 2.00-2.08 (2H,m), 1.84 (2H, d, J=7.3 Hz), 1.48-1.73 (2H, m), 1.12-1.28 (5H, m).

Example 182.(4-{4-[8-(2-Morpholin-4-yl-ethoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone,2HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=532(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.09-9.16 (1H, m), 8.72-8.86 (1H,m), 7.98-8.06 (1H, m), 7.74-7.89 (2H, m), 7.67 (2H, d, J=8.8 Hz), 7.17(2H, d, J=8.5 Hz), 4.67-4.78 (3H, m), 4.25-4.35 (2H, m), 3.91-3.98 (4H,m), 3.71-3.89 (4H, m), 3.51-3.55 (2H, m), 3.22-3.50 (5H, m), 1.93-2.13(4H, m), 1.75-1.92 (2H, m), 1.50-1.73 (2H, m).

Example 183.(4-{4-[8-(2-Pyrrolidin-1-yl-ethoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=516(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 10.67-10.91 (1H, m), 9.08-9.17 (1H,m), 8.72-8.93 (1H, m), 7.98-8.09 (1H, m), 7.77-7.92 (2H, m), 7.68 (2H,d, J=8.5 Hz), 7.18 (2H, d, J=8.5 Hz), 4.67-4.78 (2H, m), 4.15-4.24 (2H,m), 3.81-3.96 (2H, m), 3.73-3.81 (2H, m), 3.59-3.72 (2H, m), 3.49-3.57(2H, m), 3.22-3.47 (2H, m), 3.01-3.20 (2H, m), 1.96-2.11 (8H, m),1.78-1.90 (2H, m), 1.49-1.73 (2H, m).

Example 184.(4-{4-[8-(3-Pyrrolidin-1-yl-propoxy)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=530(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.07-9.14 (1H, m), 8.72-8.83 (1H,m), 7.95-8.02 (1H, m), 7.75-7.86 (2H, m), 7.67 (2H, d, J=8.8 Hz), 7.18(2H, d, J=8.5 Hz), 4.67-4.77 (2H, m), 3.93-3.98 (2H, m), 3.83-3.90 (1H,m), 3.73-3.80 (2H, m), 3.59-3.67 (2H, m), 3.33-3.50 (1H, m), 3.21-3.27(2H, m), 2.94-3.06 (2H, m), 1.97-2.10 (8H, m), 1.89-1.96 (2H, m),1.78-1.89 (2H, m), 1.51-1.71 (2H, m).

Example 185.[4-[4-[8-[2-(4-Methylpiperazin-1-yl)ethoxy]-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=545(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.09 (1H, d, J=3.5 Hz), 8.58-8.71(1H, m), 7.92-7.99 (1H, m), 7.70-7.80 (2H, m), 7.67 (2H, d, J=8.5 Hz),7.16 (2H, d, J=8.5 Hz), 4.67-4.79 (2H, m), 4.32 (2H, br. s.), 3.84-4.01(3H, m), 3.69-3.82 (4H, m), 3.20-3.66 (9H, m), 2.86 (3H, s), 1.94-2.11(4H, m), 1.78-1.91 (2H, m), 1.53-1.72 (2H, m).

Example 186.[4-[4-[8-(2-Methoxyethoxy)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=477(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.13-9.18 (1H, m), 8.92-9.00 (1H,m), 8.05 (1H, d, J=8.8 Hz), 7.90-7.97 (1H, m), 7.87 (1H, d, J=8.5 Hz),7.70 (2H, d, J=8.8 Hz), 7.17 (2H, d, J=8.5 Hz), 4.67-4.80 (2H, m),4.03-4.09 (2H, m), 3.72-3.89 (5H, m), 3.53-3.58 (2H, m), 3.27-3.40 (1H,m), 3.05 (3H, s), 1.95-2.09 (4H, m), 1.79-1.91 (2H, m), 1.50-1.72 (2H,m).

Example 187.[4-[4-[8-(3-Methoxypropoxy)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone,HCl

The product was isolated as a yellow solid. Analysis: LCMS m/z=491(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.16 (1H, d, J=4.8 Hz), 8.98 (1H, d,J=7.8 Hz), 8.06 (1H, d, J=8.8 Hz), 7.95 (1H, dd, J=8.0, 5.0 Hz), 7.87(1H, d, J=8.5 Hz), 7.66 (2H, d, J=8.8 Hz), 7.18 (2H, d, J=8.8 Hz),4.67-4.80 (2H, m), 3.93 (2H, t, J=6.5 Hz), 3.80-3.89 (2H, m), 3.71-3.80(2H, m), 3.28-3.50 (2H, m), 3.25 (2H, t, J=6.3 Hz), 3.10 (3H, s),1.94-2.10 (4H, m), 1.79-1.94 (4H, m), 1.51-1.71 (2H, m).

Example 188.1-{4-[4-(8-Hydroxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,HCl

Step 1. 7-Bromo-8-(tert-butyl-dimethyl-silanyloxy)-quinoline

A mixture of 7-bromoquinolin-8-ol (5.00 g, 22.3 mmol),tert-butyldimethylsilyl chloride (3.70 g, 24.5 mmol), DIPEA (9.72 mL,55.8 mmol), and DCM (100 mL) was stirred at rt for 3 days. The reactionwas partition in DCM (100) and H₂O (50 mL), the organic layer wasseparated then washed with brine, dried (Na₂SO₄), and concentrated. Theresidue was chromatography on silica gel (DCM) to give 7.37 g of whitesolid.

Step 2. tert-butyl4-[4-(8-hydroxy-7-quinolyl)phenoxy]piperidine-1-carboxylate

A flask charged with4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (3.0 g, 7.44 mmol),7-bromo-8-(tert-butyl-dimethyl-silanyloxy)-quinoline (2.77 g, 8.18mmol), palladium acetate (170 mg, 0.75 mmol), triphenylphosphine (0.39g, 1.49 mmol), 1.0 M of sodium carbonate in water (40 mL, 4.88 mmol),1,4-dioxane (40 mL), and DMF (40 mL) was flashed with N₂ for 25 min. Thereaction was stirred at 90° C. for 18 h and cooled to RT. The reactionmixture was portioned between EtOAc (150 mL), washed with saturatedNaHCO₃ solution (100 mL), the organic layer was separated and the waterlayer was extracted with EtOAc (100 mL). The combined organic layerswere washed with H₂O, brine, dried (Na₂SO₄), and concentrated. Theresidue was stirred in DCM (35 mL) at 0° C. and added 1.0 M oftetra-n-butylammonium fluoride in THF (4.88 mL, 4.88 mmol). After 1 h atrt, the reaction was washed with H₂O (20 mL), brine, dried (Na₂SO₄) andconcentrated. The residue was chromatography on silica gel (0-70%EtOAc/Hexanes) to give (1.03 g, 33%).

Step 3. 7-[4-(Piperidin-4-yloxy)-phenyl]-quinolin-8-ol, HCl

To a solution of tert-butyl4-[4-(8-hydroxy-7-quinolyl)phenoxy]piperidine-1-carboxylate (638 mg,1.52 mmol) in DCM (20 mL) was added 4.0 M of HCl in 1,4-dioxane (1.90mL, 7.59 mmol). After 22 h, the resulted precipitate was collected byfiltration, washed with DCM and dried to give 418 mg (77%) oflight-brown solid.

Step 4

A mixture of 7-[4-(piperidin-4-yloxy)-phenyl]-quinolin-8-ol; HCl (110mg, 0.31 mmol), propanoic acid (27 μL, 0.36 mmol), HATU (117 mg, 0.31mmol), DIPEA (244 μL, 1.40 mmol), and THF (8 mL) was stirred at rt for 1h. The reaction mixture was concentrated and the residue was purified bypre-HPLC. The product fractions were combined and neutralized with sat.NaHCO₃ solution (25 mL), extracted with DCM (3×25 mL), dried (Na₂SO₄),and concentrated. The product was dissolved in DCM (˜5 mL) and mixedwith 1.2 eq. of 2 M HCl in Et₂O and concentrated. The residue wasdissolved in a small amount of DCM and concentrated—repeated thisprocedure several times, dried to give 82 mg (64%) of off-white solid.Analysis: LCMS m/z=377 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.76-10.69(1H, m), 8.98-9.03 (1H, m), 8.70-8.78 (1H, m), 7.77-7.84 (1H, m),7.65-7.77 (4H, m), 7.10-7.17 (2H, m), 4.68-4.73 (1H, m), 3.84-3.95 (1H,m), 3.67-3.78 (1H, m), 3.21-3.43 (2H, m), 2.35 (2H, q, J=7.4 Hz),1.89-2.06 (2H, m), 1.49-1.72 (2H, m), 1.00 (3H, t, J=7.4 Hz).

The following compounds were synthesized using the procedure for Example188.

Example 189.Cyclopropyl-{4-[4-(8-hydroxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone,HCl

The product was isolated as an off-white solid. Analysis: LCMS m/z=389(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.74-10.73 (1H, m), 9.01-9.06 (1H,m), 8.77-8.84 (1H, m), 7.81-7.88 (1H, m), 7.66-7.79 (4H, m), 7.12-7.18(2H, m), 4.69-4.78 (1H, m), 3.85-4.07 (2H, m), 3.51-3.64 (1H, m),3.24-3.37 (1H, m), 1.90-2.11 (3H, m), 1.49-1.74 (2H, m), 0.67-0.79 (4H,m).

Example 190.{4-[4-(8-Hydroxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone,HCl

The product was isolated as an orange solid. Analysis: LCMS m/z=419(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.63-10.98 (1H, m), 9.01-9.06 (1H,m), 8.78-8.84 (1H, m), 7.81-7.89 (1H, m), 7.65-7.79 (4H, m), 7.11-7.18(2H, m), 4.69-4.73 (1H, m), 3.71-3.96 (4H, m), 3.22-3.51 (2H, m),1.90-2.12 (5H, m), 1.76-1.90 (2H, m), 1.49-1.72 (2H, m).

Example 191.1-[4-(2-Chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Step 1. 4-(4-Bromo-2-chloro-phenoxy)-piperidine-1-carboxylic acidtert-butyl ester

To a 0-5° C. stirred solution of triphenylphosphine (3.1 g, 11.7 mmol)and 40% w/w DEAD in toluene (5.12 mL, 13.0 mmol) in THF (25 mL) wasadded a mixture of 4-bromo-2-chloro-phenol (1.5 g, 7.2 mmol) and4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.89 g, 9.39mmol) in THF (5 mL) under argon. The cooling bath was removed and thereaction stirred at rt for 20 h, concentrated, then stirred with etherand filtered. The filtrate was concentrated in vacuo and the productpurified by silica gel column chromatography (0-20% EtOAC in hexanes) togive 2.30 g (81%). Analysis: LCMS=291 (M-100-BOC).

Step 2. 4-(2-Chloro-4-quinolin-3-yl-phenoxy)-piperidine-1-carboxylicacid tert-butyl ester

A 50 mL R. B. flask charged with 1,4-dioxane (2.5 mL),triphenylphosphine (0.119 g, 0.454 mmol), and palladium acetate (0.026g, 0.12 mmol) was stirred at rt for 15 min.4-(4-bromo-2-chloro-phenoxy)-piperidine-1-carboxylic acid tert-butylester (0.89 g, 2.3 mmol), 3-quinolineboronic acid (0.59 g, 3.4 mmol),DMF (3.00 mL) and 1M aqueous sodium carbonate (5 mL) were added andflushed with argon five times. The reaction mixture was heated at 80° C.for 7 h and concentrated. The residue was suspended in a mixture of 1MNa₂CO₃ and EtOAc and then filtered through a pad of celite/silica gel.The filtrate was separated and the aqueous layer was extracted twicewith EtOAc. The combined organics was washed with brine, dried,filtered, and evaporated to give a crude product. The product waspurified by silica gel chromatography using 0-5% MeOH in DCM to give0.90 g (90%). Analysis: LCMS m/z 439 (M+H).

Step 3. 3-[3-Chloro-4-(piperidin-4-yloxy)-phenyl]-quinoline

To a stirred solution of4-(2-chloro-4-quinolin-3-yl-phenoxy)-piperidine-1-carboxylic acidtert-butyl ester (0.90 g, 2.0 mmol) in DCM (15.00 mL) was added 4M HClin dioxane (2 mL, 23.1 mmol) at rt. The reaction mixture was stirred atrt for 17 h and evaporated. The crude product was treated twice withEtOAc and evaporated, then crystallized from a mixture of DCM, MeOH, andether to produce 3-[3-chloro-4-(piperidin-4-yloxy)-phenyl]-quinoline,0.67 g (96%) as a yellow solid. Analysis: mp: 274-276° C. (DCM, ether,and MeOH); ¹H NMR (DMSO-d₆) δ: 9.54 (d, 1H, J=2 Hz), 9.2-9.35 (brs, 2H),9.19 (s, 1H), 8.30 (d, 1H, J=8 Hz), 8.23 (d, 1H, J=8 Hz), 8.15 (d, 1H,J=2 Hz), 7.93-8.03 (m, 2H), 7.85 (t, 1H, J=7 Hz), 7.50 (d, 1H, J=9 Hz),4.88-4.99 (m, 1H), 3.05-3.30 (m, 4H), 2.12-2.27 (m, 2H), 1.89-2.03 (m,2H).

Step 4.1-[4-(2-Chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one

To a stirred solution of3-[3-chloro-4-(piperidin-4-yloxy)-phenyl]-quinoline (0.125 g, 0.369mmol) 2HCl and DIPEA (0.450 mL, 2.58 mmol) in DCM (3.00 mL) was addedpropanoyl chloride (0.0641 mL, 0.738 mmol) at rt. The reaction mixturewas stirred for 2 h and evaporated. The crude product was purified byGilson. The product was stirred with 4M HCl in dioxane (1 mL) for 15 minand crystallized from a mixture of DCM, MeOH, and ether and dried at 60°C. for 16 h to give a yellow solid (0.1 g, 68%). Analysis: mp: 183-185°C.; LCMS m/z 395 (M+1); ¹H NMR (DMSO-d₆) δ: 9.46 (d, 1H, J=2 Hz), 9.04(s, 1H), 8.14-8.23 (m, 2H), 8.10 (d, 1H, J=2 Hz), 7.88-7.98 (m, 2H),7.79 (t, 1H, J=7 Hz), 7.47 (d, 1H, 9 Hz), 4.84-4.93 (m, 1H), 3.63-3.77(m, 2H), 3.38-3.53 (m, 2H), 2.37 (q, 2H, J=7 Hz), 1.85-2.04 (m, 2H),1.57-1.80 (m, 2H), 1.00 (t, 3H, J=7 Hz).

The following examples were synthesized using the method for Example191.

Example 192.1-[4-(2-Chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one

Analysis: LCMS m/z 409 (M+1); ¹H NMR (DMSO-d₆) δ: 9.56 (d, 1H, J=2 Hz),9.23 (s, 1H), 8.31 (d, 1H, J=8 Hz), 8.25 (d, 1H, J=8 Hz), 8.14 (d, 1H,J=2 Hz), 7.96-8.07 (m, 1H), 7.93-7.96 (m, 1H), 7.86 (t, 1H, J=8 Hz),7.49 (d, 1H, J=9 Hz), 4.85-4.96 (m, 1H), 3.68-3.80 (m, 2H), 3.40-3.58(m, 2H), 2.83-2.99 (m, 1H), 1.82-2.05 (m, 2H), 1.52-1.78 (m, 2H), 1.01(d, 6H, J=7 Hz).

Example 193.[4-(2-Chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-cyclopropyl-methanone

Analysis: LCMS m/z 407 (M+1); ¹H NMR (DMSO-d₆) δ: 9.58 (s, 1H), 9.20 (s,1H), 8.29 (d, 1H, J=8 Hz), 8.24 (d, 1H, J=8 Hz), 8.15 (s, 1H), 7.90-8.09(m, 2H), 7.85 (t, 1H, J=8 Hz), 7.50 (d, 1H, J=8 Hz), 4.87-4.96 (m, 1H),3.34-4.06 (m, 4H), 1.81-2.07 (m, 3H), 1.53-1.81 (m, 2H), 0.65-0.82 (m,4H).

Example 194.1-[4-(2-Chloro-4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z 395 (M+1); ¹H NMR (DMSO-d₆) δ: 9.19 (d, 1H, J=3 Hz),8.90 (d, 1H, J=8 Hz), 8.44 (s, 1H), 8.31 (d, 1H, J=8 Hz), 8.21 (d, 1H,J=1H), 8.00 (d, 1H, J=2 Hz), 7.79-7.93 (m, 2H), 7.47 (d, 1H, J=9 Hz),4.82-4.92 (m, 1H), 3.62-3.78 (m, 2H), 3.37-3.51 (m, 2H), 2.36, (q, 2H,J=7 Hz), 1.85-2.41 (m, 2H), 1.55-1.80 (m, 2H), 1.00 (t, 3H, J=7 Hz).

Example 195.1-[4-(2-Chloro-4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one

Analysis: LCMS m/z 409 (M+1); ¹H NMR (DMSO-d₆) δ: 9.15-9.24 (m, 1H),8.85-8.97 (m, 1H), 8.40-8.49 (m, 1H), 8.27-8.37 (m, 1H), 8.16-8.25 (m,1H), 7.99 (d, 1H, J=2 Hz), 7.70-7.83 (m, 2H), 7.47 (d, 1H, J=8 Hz),4.83-4.92 (m, 1H), 3.34-3.83 (m, 4H), 2.87-2.98 (m, 1H), 1.83-2.08 (m,2H), 1.56-1.80 (m, 2H), 1.01 (d, 6H, J=7 Hz).

Example 196.1-[4-(2-Methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=391 (M+1); ¹H NMR (DMSO-d₆) δ: 9.51 (d, 1H, J=2 Hz),9.11 (s, 1H), 7.95 (t, 1H, J=8 Hz), 7.82 (t, 1H, J=8 Hz), 7.57 (d, 1H,J=2 Hz), 7.50 (d, 1H, J=8 Hz), 7.26 (d, 1H, J=8 Hz), 4.60-4.69 (m, 1H),3.81-4.00 (m, 4H), 3.63-3.79 (m, 1H), 3.21-3.42 (m, 2H), 2.34 (q, 2H,J=7 Hz), 1.82 (m, 2H, 1.45-1.69 (m, 2H) 1.00 (t, 3H, J=7 Hz).

Example 197.1-[4-(2-Methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one

Analysis: LCMS m/z=405 (M+1); ¹H NMR (DMSO-d₆) δ: 9.46 (d, 1H, J=2 Hz),9.01 (s, 1H), 8.18 (d, 1H, J=8 Hz), 7.91 (t, 1H, J=7 Hz), 7.79 (t, 1H,J=7 Hz), 7.56 (d, 1H, J=2 Hz), 7.47 (d, 1H, J=8 Hz), 7.26 (d, 1H, J=8Hz), 4.61-4.68 (m, 1H), 3.75-3.97 (m, 5H), 3.20-3.48 (m, 2H), 2.84-2.96(m, 1H), 1.82-2.05 (m, 2H), 1.45-1.68 (m, 2H), 1.01 (d, 6H, J=7 Hz).

Example 198.Cyclopropyl-[4-(2-methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS m/z=403 (M+1); ¹H NMR (DMSO-d₆) δ: 9.55 (d, 1H, J=2 Hz),9.15 (s, 1H), 8.20-8.32 (m, 2H), 7.98 (t, 1H, J=8 Hz), 7.85 (t, 1H, J=8Hz), 7.60 (d, 1H, J=2 Hz), 7.52 (d, 1H, J=8 Hz), 7.29 (d, 1H, J=8 Hz),4.64-4.75 (m, 1H), 3.80-4.10 (m, 5H), 3.48-3.63 (m, 1H), 3.21-3.39 (m,1H), 1.84-2.15 (m, 3H), 1.43-1.78 (m, 2H), 0.67-0.82 (4H).

Example 199.1-[4-(2-Methoxy-4-quinolin-7-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=391 (M+1); ¹H NMR (DMSO-d₆) δ: 9.15 (d, 1H, J=5 Hz),8.90 (d, 1H, J=8 Hz), 8.43 (s, 1H), 8.29 (d, 1H, J=9 Hz), 8.22 (d, 1H,J=9 Hz), 7.82-7.91 (m, 1H), 7.47 (d, 1H, J=2 Hz), 7.42 (d, 1H, J=8 Hz),7.25 (d, 1H, J=8 Hz), 4.60-4.70 (m, 1H), 3.84-3.95 (m, 5H), 3.64-3.84(m, 2H), 3.20-3.30 (m, 2H), 2.35 (q, 2H, J=7 Hz), 1.83-2.04 (m, 2H),1.45-1.71 (m, 2H), 1.00 (t, 3H, J=7 Hz).

Example 200.1-[4-(3-Fluoro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z 379 (M+1); ¹H NMR (DMSO-d₆) δ: 9.24 (s, 1H), 8.85 (s,1H), 8.20 (d, 1H, J=9 Hz), 7.94 (t, 1H, J=7 Hz), 7.79 (t, 1H, J=7 Hz),7.71 (t, 1H, J=9 Hz), 7.16 (dd, 1H, J=2 Hz, J=13 Hz), 7.06 (dd, 1H, J=2Hz, J=9 Hz), 4.73-4.82 (m, 1H), 3.84-3.97 (m, 2H), 3.65-3.79 (m, 2H),3.18-3.42 (m, 2H), 2.35 (q, 2H, J=7 Hz), 1.89-2.07 (m, 2H), 1.46-1.70(m, 2H), 1.00 (t, 3H, 7 Hz).

Example 201.1-[4-(3-Fluoro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methylpropan-1-one

Analysis: LCMS m/z=393 (M+1). ¹H NMR (DMSO-d₆) δ: 9.23 (s, 1H), 8.81 (s,1H), 8.18 (d, 2H, J=8 Hz), 7.94 (t, 1H, J=7 Hz), 7.78 (t, 1H, J=8 Hz),7.73 (t, 1H, J=9 Hz), 7.16 (dd, 1H, J=2 Hz, J=9 Hz), 7.06 (dd, 1H, J=2Hz, J=8 Hz), 4.74-4.83 (m, 1H), 3.86-3.97 (m, 1H), 3.74-3.85 (m, 1H),3.35-3.47 (m, 1H), 3.19-3.31 (m, 1H), 2.84-2.97 (m, 1H), 1.89-2.09 (m,2H, 1.47-1.70 (m, 2H), 1.01 (d, 6H, J=7 Hz).

Example 202.Cyclopropyl-[4-(3-fluoro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMs m/z=391 (M+1); ¹H NMR (DMSO-d₆) δ: 9.23 (s, 1H), 8.81 (s,1H), 8.13-8.23 (m, 2H), 7.93 (t, 1H, J=8 Hz), 7.67-7.82 (m, 2H), 7.17(dd, 1H, J=2 Hz), J=13 Hz), 7.07 (dd, 1H, J=2 Hz), J=9 Hz), 4.73-4.87(m, 1H), 3.82-4.10 (m, 2H), 3.47-3.65 (m, 1H), 3.19-3.36 (m, 1H),1.87-2.14 (m, 3H), 1.45-1.75 (m, 2H), 0.64-0.79 (m, 4H).

Example 203.1-[4-(3-Chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=395 (M+1); ¹H NMR (DMSO-d₆) δ: 9.16 (s, 1H), 8.75 (s,1H), 8.15-8.25 (m, 2H), 7.96 (t, 1H, J=7 Hz), 7.79 (t, 1H, J=7 Hz), 7.58(d, 1H, J=8 Hz), 7.34 (d, 1H, J=2 Hz), 7.19 (dd, 1H, J=2 Hz, J=9 Hz),4.74-4.84 (m, 1H), 3.83-3.96 (m, 2H), 3.21-3.42 (m, 2H), 2.35 (q, 2H,J=7 Hz), 1.88-2.07 (m, 2H), 1.46-1.70 (m, 2H, 1.00 (t, 3H, J=7 Hz).

Example 204.1-[4-(3-Chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one

Analysis: LCMS m/z=409 (M+1); ¹H NMR (DMSO-d₆) δ: 9.16 (d, 1H, J=2 Hz),8.76 (s, 1H), 8.20 (t, 1H, J=8 Hz), 7.96 (t, 1H, J=8 Hz), 7.80 (t, 1H,J=8 Hz), 7.59 (d, 1H, J=8 Hz), 7.35 (d, 1H, J=2 Hz), 7.19 (dd, 1H, J=2Hz, J=9 Hz), 4.75-4.85 (m, 1H), 3.74-3.97 (m, 2H), 3.35-3.48 (m, 1H),3.20-3.33 (m, 1H), 2.84-2.97 (m, 1H), 1.88-2.09 (m, 2H), 1.46-1.70 (m,2H), 1.00 (d, 6H, J=7 Hz).

Example 205.[4-(3-Chloro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-cyclopropyl-methanone

Analysis: LCMS m/z 407 (M+1); ¹H NMR (DMSO-d₆) δ: 9.12 (s, 1H), 8.70 (s,1H), 8.17 (t, 2H, J=7 Hz), 7.93 (t, 1H, J=7 Hz), 7.77 (t, 1H, J=7 Hz),7.58 (d, 1H, J=8 Hz), 7.34 (s, 1H), 7.19 (d, 1H, J=7 Hz), 4.75-4.88 (m,1H), some peaks merged with Water peak, 3.19-3.37 (m, 1H), 1.87-2.13 (m,3H), 1.44-1.75 (m, 2H), 0.63-0.80 (m, 4H).

Example 206.2-Methyl-1-[4-(3-methyl-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=389 (M+1); ¹H NMR (DMSO-d₆) δ: 9.17 (d, 1H, J=2 Hz),8.80 (s, 1H), 8.17-8.30 (m, 2H), 7.99 (t, 1H, J=8 Hz), 7.83 (t, 1H, J=7Hz), 7.37 (d, 1H, J=8 Hz), 6.97-7.09 (m, 2H), 4.67-4.78 (m, 1H),3.72-3.96 (m, 2H), 3.21-3.48 (m, 2H), 2.83-2.98 (m, 1H), 2.32 (s, 3H),1.87-2.08 (m, 2H), 1.44-1.71 (m, 2H), 1.01 (d, 6H, J=7 Hz).

Example 207.1-[4-(3-Methyl-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=375 (M+1); ¹H NMR (DMSO-d₆) δ: 9.14 (d, 1H, J=2 Hz),8.74 (s, 1H), 8.20 (t, 2 Hz, J=8 Hz), 7.96 (t, 1H, J=7 Hz), 7.81 (t, 1H,J=7 Hz), 7.36 (d, 1H, J=9 Hz), 6.96-7.08 (m, 2H), 4.65-4.75 (m, 1H),3.82-3.94 (m, 2H), 3.65-3.77 (m, 2H), 3.21-3.42 (m, 2H), 2.35 (q, 2H,J=7 Hz), 2.31 (s, 3H), 1.87-2.05 (m, 2H), 1.46-1.70 (m, 2H), 1.00 (t,3H, J=7 Hz).

Example 208.4-(3-Methyl-4-quinolin-3-yl-phenoxy)-piperidine-1-carboxylic acid methylester

Analysis: LCMS m/z=377 (M+1); ¹H NMR (DMSO-d₆) δ: 9.15 (d, 1H, J=2H),8.79 (s, 1H), 8.22 (t, 2H, J=8 Hz), 7.98 (t, 1H, J=8 Hz), 7.83 (t, 2H,J=8 Hz), 7.36 (d, 1H, J=8 Hz), 6.96-7.07 (m, 2H), 4.62-4.73 (m, 1H),3.65-3.79 (m, 2H), 3.22-3.36 (m, 2H), 2.31 (s, 3H), 1.90-2.10 (m, 2H),1.52-1.66 (m, 2H).

Example 209.1-[4-(3-Methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=391 (M+1); ¹H NMR (DMSO-d₆) δ: 9.22 (d, 1H, J=2 Hz),8.79 (s, 1H), 8.18 (d, 2H, J=8 Hz), 7.93 (t, 1H, J=8 Hz), 7.78 (t, 1H,J=8 Hz), 7.50 (d, 1H, J=8 Hz), 6.75-6.85 (m, 2H), 4.70-4.82 (m, 1H),3.80-3.96 (m, 2H), 3.84 (s, 3H), 3.22-3.44 (m, 2H), 2.35 (d, 2H, J=8Hz), 1.87-2.08 (m, 2H), 1.46-1.73 (m, 2H), 1.00 (t, 3H, J=7 Hz).

Example 210.1-[4-(3-Methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one

Analysis: LCMS m/z=405 (M+1); ¹H NMR (DMSO-d₆) δ: 9.23 (d, 1H, J=2 Hz),8.81 (s, 1H), 8.13-8.23 (m, 2H), 7.93 (t, 1H, J=8 Hz), 7.78 (t, 1H, J=8Hz), 7.50 (d, 1H, J=8 Hz), 6.77-6.85 (m 2H), 4.73-4.84 (m, 1H),3.73-3.95 (m, 2H), 3.84 (s, 3H), 3.23-3.49 (m, 2H), 2.85-2.97 (m, 1H),1.88-2.09 (m, 2H), 1.46-1.71 (m, 2H), 1.01 (d, 6H, J=6 Hz).

Example 211.Cyclopropyl-[4-(3-methoxy-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS m/z=403 (M+1); ¹H NMR (DMSO-d₆) δ: 9.19 (d, 1H, J=2 Hz),8.73 (s, 1H), 8.15 (d, 2H, J=8 Hz), 7.90 (t, 1H, J=8 Hz), 7.76 (t, 1H,J=8 Hz), 7.49 (d, 1H, J=8 Hz), 6.77-6.86 (m, 2H), 4.73-4.84 (m, 1H),3.80-4.07 (m, 2H), 3.84 (s, 3H), 3.49-3.66 (m, 1H), 3.23-3.39 (m, 1H),1.87-2.13 (m, 3H), 1.46-1.76 (m, 2H), 0.63-0.79 (m, 4H).

Example 212.1-[4-(2-Methyl-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=375 (M+1); ¹H NMR (DMDSO-d₆) δ: 9.47 (s, 1H, J=2 Hz),9.06 (s, 1H), 8.22 (d, 2H, J=8 Hz), 7.94 (t, 1H, J=7 Hz), 7.86-7.73 (m,3H), 7.24 (d, 1H, J=8 Hz), 4.83-4.73 (m, 1H), 3.80-3.59 (m, 2H),3.50-3.37 (m, 2H), 2.36 (q, 2H, J=7 Hz), 2.29 (s, 3H), 2.04-1.84 (m,2H), 1.76-1.54 (m, 2H), 1.01 (t, 3H, J=7 Hz).

Example 213.2-Methyl-1-[4-(2-methyl-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=389 (M+1); ¹H NMR (DMSO-d₆) δ: 9.37 (d, 1H, J=2 Hz),8.86 (s, 1H), 8.13 (t, 2H, J=7 Hz), 7.86 (t, 1H, 7 Hz), 7.68-7.81 (m,3H), 7.22 (d, 1H, J=8 Hz), 4.72-4.83 (m, 1H), 2.84-2.97 (m, 1H), 2.29(s, 3H), 1.84-2.06 (m, 2H), 1.51-1.77 (m, 2H), 1.01 (d, 6H, J=7 Hz).

Example 214.Cyclopropyl-[4-(2-methyl-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS m/z=386 (M+1); ¹H NMR (DMSO-d₆) δ: 9.43 (d, 1H, J=2 Hz),8.98 (s, 1H), 8.18 (d, 2H, J=9 Hz), 7.91 (t, 1H, J=7 Hz), 7.71-7.84 (m,3H), 7.23 (d, 1H, J=8 Hz), 4.74-4.85 (m, 1H), some peaks merged withH₂O, 2.29 (s, 3H), 1.82-2.10 (m, 3H), 1.52-1.81 (m, 2H).

Example 215.1-[4-(2,5-Difluoro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=397 (M+1); ¹H NMR (DMSO-d₆) δ: 9.17 (s, 1H), 8.72 (s,1H), 8.12 (d, 2H, J=9 Hz), 7.84-7.91 (m, 1H), 7.69-7.81 (m, 2H),7.47-7.56 (m, 1H), 4.75-4.85 (m, 1H), 3.66-3.77 (m, 2H), 3.20-3.41 (m,2H), 2.35 (q, 2H, J=7 Hz), 1.90-2.09 (m, 2H), 1.49-1.74 (m, 2H), 1.00(t, 3H, J=7 Hz).

Example 216.1-[4-(2,5-Difluoro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-2-methyl-propan-1-one

Analysis: LCMS m/z=411 (M+1); ¹H NMR (DMSO-d₆) δ: 9.20 (d, 1H, J=2 Hz),8.77 (s, 1H), 8.14 (d, 2H, J=9 Hz), 7.90 (t, 1H, J=7 Hz), 7.72-7.82 (m,2H), 7.48-7.57 (m, 1H), 4.76-4.86 (m, 1H), 3.77-4.00 (m, 2H), 3.41 (t,1H, J=10 Hz), 3.25 (t, 1H, J=9 Hz), 2.83-2.98 (m, 1H), 1.91-2.12 (m,2H), 1.49-1.74 (m, 2H), 1.01 (d, 6H, J=7 Hz).

Example 217.Cyclopropyl-[4-(2,5-difluoro-4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS m/z=409 (M+1); ¹H NMR (DMSO-d₆) δ: 9.15 (t, 1H, 2H), 8.69(s, 1H), 8.10 (d, 2H, J=9 Hz), 7.86 (t, 1H, J=7 Hz), 7.68-7.80 (m, 2H),7.47-7.57 (m, 1H), 4.77-4.87 (m, 1H), 3.84-4.09 (m, 2H), 3.20-3.36 (m,1H), 1.90-2.15 (m, 3H), 1.49-1.77 (m, 2H), 0.65-0.79 (m, 4H).

Example 218.3-Oxo-3-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propionitrile

To a 25 mL R. B. flask was charged with cyanoacetic acid (0.04 g, 0.47mmol), 3-[4-(piperidin-4-yloxy)-phenyl]-quinoline (0.11 g, 0.36 mmol),acetonitrile (2 mL), DIPEA (0.504 mL, 2.89 mmol), and HATU (0.302 g,0.795 mmol). The reaction mixture was stirred at rt and monitored byHPLC and LCMS methods. After completion, the reaction mixture wasevaporated in vacuo. to obtain a crude product. The crude product waspurified by Gilson and then lyophilized to produce3-Oxo-3-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-propionitrile,0.102 g (60%). Analysis: LCMS m/z=372 (M+1); ¹H NMR (DMSO-d₆) δ: 9.34(d, 1H, J=2 Hz), 8.80 (s, 1H), 8.10 (t, 2H, J=9 Hz), 7.80-7.92 (m, 3H),7.71 (t, 1H, J=8 Hz), 7.19 (d, 2H, J=8 Hz), 4.70-4.80 (m, 1H), 4.08 (s,2H), 3.78-3.89 (m, 1H), 3.54-3.65 (m, 1H), 3.27-3.40 (m, 2H), 1.90-2.08(m, 2H), 1.65-1.77 (m, 1H), 1.53-1.65 (m, 1H).

Example 219.1-{4-[2-Fluoro-4-(8-methoxy-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=409 (M+1); ¹H NMR (DMSO-d₆) δ: 9.04-9.11 (m, 1H) 8.72(d, J=8.28 Hz, 1H) 7.95 (d, J=8.53 Hz, 1H) 7.75-7.83 (m, 2H) 7.60 (dd,J=12.55, 2.01 Hz, 1H) 7.38-7.53 (m, 2H) 4.74 (dt, J=7.84, 3.98 Hz, 1H)3.86-3.97 (m, 1H) 3.85 (s, 3H) 3.66-3.78 (m, 1H) 3.22-3.42 (m, 2H) 2.36(q, J=7.45 Hz, 2H) 1.91-2.09 (m, 2H) 1.51-1.75 (m, 2H) 1.01 (t, J=7.40Hz, 3H).

Example 220.Cyclopropyl-{4-[2-fluoro-4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=421 (M+1); ¹H NMR (DMSO-d₆) δ: 9.05 (dd, J=4.52, 1.51Hz, 1H) 8.67 (d, J=8.03 Hz, 1H) 7.92 (d, J=8.53 Hz, 1H) 7.71-7.80 (m,2H) 7.59 (dd, J=12.80, 2.01 Hz, 1H) 7.38-7.52 (m, 2H) 4.76 (dt, J=7.72,4.05 Hz, 1H) 3.81-4.09 (m, 5H) 3.57 (br. s., 1H) 3.30 (br. s., 1H)1.90-2.14 (m, 3H) 1.49-1.79 (m, 2H) 0.63-0.82 (m, 4H).

Example 221.{4-[2-Fluoro-4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

A 50 mL R.B flask charged with7-[3-fluoro-4-(piperidin-4-yloxy)-phenyl]-8-methoxyquinoline (0.237 g,0.673 mmol), (R)-tetrahydrofuran-2-carboxylic acid (0.091 g, 0.79 mmol),HATU (0.30 g, 0.79 mmol), Et₃N (0.55 mL, 3.9 mmol) and DCM (3 mL) wasstirred at rt 1.5 h. The reaction mixture was concentrated, andpartitioned between EtOAc and saturated aqueous NaHCO₃. The aqueouslayer was extracted twice with EtOAc and the combined organics waswashed with brine, dried, filtered, and concentrated to give a crudeproduct that was purified by Gilson to produce{4-[2-fluoro-4-(8-methoxyquinolin-7-yl)-phenoxy]piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone,85 mg (28%). Analysis: LCMS m/z=451 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ:9.06 (dd, J=4.52, 1.51 Hz, 1H) 8.68 (d, J=8.03 Hz, 1H) 7.93 (d, J=8.53Hz, 1H) 7.72-7.80 (m, 2H) 7.59 (dd, J=12.55, 2.01 Hz, 1H) 7.38-7.52 (m,2H) 5.76 (s, 2H) 4.65-4.81 (m, 4H) 3.70-3.96 (m, 8H) 3.20-3.52 (m, 2H)1.92-2.13 (m, 4H) 1.77-1.91 (m, 2H) 1.51-1.75 (m, 2H).

Example 222.{4-[4-(8-Chloroquinolin-7-yl)-2-fluorophenoxy]-piperidin-1-yl}-cyclopropyl-methanone

Analysis: LCMS m/z=425 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.08 (dd,J=4.14, 1.63 Hz, 1H) 8.51 (dd, J=8.28, 1.76 Hz, 1H) 8.05 (d, J=8.53 Hz,1H) 7.63-7.73 (m, 2H) 7.49 (dd, J=12.30, 2.26 Hz, 1H) 7.39-7.46 (m, 1H)7.31-7.38 (m, 1H) 4.76 (tt, J=7.81, 3.73 Hz, 1H) 3.83-4.10 (m, 2H) 3.57(br. s., 1H) 3.29 (br. s., 1H) 1.90-2.15 (m, 3H) 1.50-1.80 (m, 2H)0.65-0.81 (m, 4H).

Example 223.{4-[4-(8-Chloroquinolin-7-yl)-2-fluorophenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=455 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.07 (dd,J=4.27, 1.76 Hz, 1H) 8.51 (dd, J=8.28, 1.76 Hz, 1H) 8.05 (d, J=8.53 Hz,1H) 7.62-7.73 (m, 2H) 7.49 (dd, J=12.17, 2.13 Hz, 1H) 7.38-7.45 (m, 1H)7.31-7.37 (m, 1H) 4.66-4.81 (m, 2H) 3.69-3.97 (m, 4H) 3.20-3.52 (m, 2H)1.92-2.14 (m, 4H) 1.77-1.91 (m, 2H) 1.50-1.77 (m, 2H).

Example 224.1-{4-[4-(8-Chloroquinolin-7-yl)-2-fluorophenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=413 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.03-9.11 (m,1H) 8.51 (dd, J=8.28, 1.76 Hz, 1H) 8.05 (d, J=8.53 Hz, 1H) 7.62-7.72 (m,2H) 7.48 (dd, J=12.17, 2.13 Hz, 1H) 7.41 (d, J=8.78 Hz, 1H) 7.35 (d,J=1.25 Hz, 1H) 4.74 (dt, J=7.91, 4.08 Hz, 2H) 3.84-3.97 (m, 1H)3.66-3.79 (m, 1H) 3.21-3.43 (m, 2H) 2.36 (q, J=7.53 Hz, 2H) 1.98 (d,J=18.57 Hz, 2H) 1.51-1.75 (m, 2H) 1.01 (t, J=7.40 Hz, 3H).

Example 225.1-{4-[2-Fluoro-4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=393 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.04 (dd,J=4.52, 1.76 Hz, 1H) 8.55 (dd, J=8.16, 1.38 Hz, 1H) 7.95 (d, J=8.28 Hz,1H) 7.68 (dd, J=8.28, 4.52 Hz, 1H) 7.57 (d, J=8.53 Hz, 1H) 7.33-7.44 (m,2H) 7.22 (dt, J=8.47, 1.04 Hz, 1H) 4.72 (dt, J=7.78, 4.14 Hz, 1H)3.84-3.96 (m, 1H) 3.67-3.78 (m, 1H) 3.21-3.43 (m, 2H) 2.69 (s, 3H)2.30-2.42 (m, 2H) 1.90-2.08 (m, 2H) 1.51-1.75 (m, 2H) 1.01 (t, J=7.40Hz, 3H).

Example 226.{4-[2-Fluoro-4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=435 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.03 (dd,J=4.27, 1.76 Hz, 1H) 8.53 (d, J=8.28 Hz, 1H) 7.94 (d, J=8.28 Hz, 1H)7.67 (dd, J=8.28, 4.27 Hz, 1H) 7.56 (d, J=8.53 Hz, 1H) 7.33-7.44 (m, 2H)7.22 (dd, J=8.41, 1.13 Hz, 1H) 4.66-4.78 (m, 2H) 3.70-3.98 (m, 4H)3.20-3.53 (m, 2H) 2.69 (s, 3H) 1.92-2.14 (m, 4H) 1.77-1.91 (m, 2H)1.51-1.76 (m, 2H).

Example 227.Cyclopropyl-{4-[2-fluoro-4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=405 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.04 (dd,J=4.27, 1.76 Hz, 1H) 8.54 (dd, J=8.28, 1.51 Hz, 1H) 7.95 (d, J=8.28 Hz,1H) 7.67 (dd, J=8.28, 4.52 Hz, 1H) 7.57 (d, J=8.53 Hz, 1H) 7.33-7.45 (m,2H) 7.23 (dt, J=8.41, 1.07 Hz, 1H) 4.74 (dt, J=7.84, 3.98 Hz, 1H)3.82-4.09 (m, 2H) 3.57 (br. s., 1H) 3.29 (br. s., 1H) 2.70 (s, 3H)1.88-2.14 (m, 3H) 1.50-1.78 (m, 2H) 0.62-0.81 (m, 4H).

Example 228.1-{4-[2-Fluoro-4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=393 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.04 (dd,J=4.27, 1.76 Hz, 1H) 8.54 (dd, J=8.28, 1.51 Hz, 1H) 7.95 (d, J=8.28 Hz,1H) 7.67 (dd, J=8.28, 4.52 Hz, 1H) 7.57 (d, J=8.53 Hz, 1H) 7.33-7.45 (m,2H) 7.23 (dt, J=8.41, 1.07 Hz, 1H) 4.74 (dt, J=7.84, 3.98 Hz, 1H)3.82-4.09 (m, 2H) 3.57 (br. s., 1H) 3.29 (br. s., 1H) 2.70 (s, 3H)1.88-2.14 (m, 3H) 1.50-1.78 (m, 2H) 0.62-0.81 (m, 4H).

Example 229.Cyclopropyl-{4-[2-fluoro-4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=405 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.95 (s, 1H)8.34 (d, J=7.78 Hz, 1H) 8.14 (d, J=7.78 Hz, 1H) 7.90-7.98 (m, 1H)7.78-7.86 (m, 1H) 7.42-7.52 (m, 2H) 7.30 (dd, J=8.41, 1.13 Hz, 1H)4.73-4.82 (m, 1H) 3.83-4.09 (m, 2H) 3.58 (br. s., 1H) 3.30 (br. s., 1H)2.73 (s, 3H) 1.90-2.15 (m, 3H) 1.50-1.79 (m, 2H) 0.65-0.80 (m, 4H).

Example 230.{4-[2-Fluoro-4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=435 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.92 (s, 1H)8.32 (d, J=8.03 Hz, 1H) 8.12 (d, J=8.28 Hz, 1H) 7.91 (t, J=7.65 Hz, 1H)7.75-7.85 (m, 1H) 7.39-7.52 (m, 2H) 7.29 (d, J=8.28 Hz, 1H) 4.66-4.82(m, 3H) 3.68-3.97 (m, 6H) 3.20-3.53 (m, 3H) 2.72 (s, 3H) 1.92-2.12 (m,4H) 1.77-1.92 (m, 2H) 1.52-1.77 (m, 2H).

Example 231.1-{4-[4-(4-Aminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1. 4-[4-(4-Aminoquinolin-3-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester

A 50 mL R. B. flask charged with 1,4-dioxane (5.00 mL),triphenylphosphine (0.0941 g, 0.359 mmol) and palladium acetate (0.0201g, 0.0896 mmol) was stirred at rt for 15 min under an argon atmosphere.4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (0.796 g, 1.97 mmol), 3-bromo-quinolin-4-ylamine(0.4 g, 2 mmol), DMF (5.00 mL) and aqueous 1M sodium carbonate (7 mL)were added and flushed with argon five times. The reaction mixture washeated at 80° C. for 7 h and concentrated. The crude residue wassuspended in a mixture of aqueous 1M Na₂CO₃ and EtOAc and then filteredthrough a pad of celite/silica gel, washed with EtOAc. The filtrate wasseparated and the aqueous layer was extracted twice with EtOAc. Thecombined organics was washed with brine, dried (Na₂SO₄), filtered, andevaporated to give a product that was used for the next reaction withoutfurther purification. Analysis: LCMS m/z=420 (M+1).

Step 2.4-{4-[4-(2,2,2-Trifluoroacetylamino)-quinolin-3-yl]-phenoxy}-piperidine-1-carboxylicacid tert-butyl ester

To an ice cold (0° C.) stirred solution of4-[4-(4-amino-quinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester (1.2 g, 2.9 mmol) and triethylamine (1.2 mL, 8.6 mmol)in DCM (10 mL) was added trifluoroacetic anhydride (0.52 mL, 3.7 mmol).The reaction mixture was stirred at rt for 1.5 h and then evaporated.The residue was partitioned between the saturated aqueous NaHCO₃ andEtOAc and the aqueous layer was extracted twice with EtOAc. The combinedorganics was washed with brine, dried, filtered, and evaporated toproduce a crude product. The product was crystallized from a mixture ofDCM, MeOH, ether and hexane to produce4-{4-[4-(2,2,2-trifluoroacetylamino)-quinolin-3-yl]-phenoxy}-piperidine-1-carboxylicacid tert-butyl ester, (0.7 g, 76%). Analysis: LCMS m/z=516 (M+1); ¹HNMR (400 MHz, CDCl₃) δ: 8.95 (s, 1H) 8.15-8.23 (m, 1H) 7.93-8.07 (m, 1H)7.75-7.83 (m, 2H) 7.63-7.71 (m, 1H) 7.33 (d, J=8.78 Hz, 2H) 7.04 (d,J=8.78 Hz, 2H) 4.51-4.59 (m, 1H) 3.66-3.77 (m, 2H) 3.31-3.42 (m, 2H)1.89-2.02 (m, 2H) 1.73-1.85 (m, 2H) 1.57 (br. s., 2H) 1.47 (s, 9H).

Step 3.1-{4-[4-(4-Aminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

To a solution of4-{4-[4-(2,2,2-Trifluoroacetylamino)-quinolin-3-yl]-phenoxy}-piperidine-1-carboxylicacid tert-butyl ester (0.34 g, 0.66 mmol) in DCM (5 mL) was addedtrifluoroacetic Acid (1.5 mL, 19 mmol) dropwise at rt. After completion,the reaction was evaporated and concentrated twice with EtOAc. To asolution of the above product and DIPEA (0.80 mL, 4.6 mmol) in DCM (5mL, 80 mmol) was added propanoyl chloride (0.07 mL, 0.8 mmol) at rt.After 2 h the reaction was concentrated and was used in the next stepwithout further purification.

Step 4.1-{4-[4-(4-Aminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

A solution of the above material and K₂CO₃ (1.5 g, 11 mmol) in methanol(8 mL) and water (2 mL) was heated at 65° C. for 2 days. Aftercompletion, the reaction mixture was concentrated and partitionedbetween EtOAc and water. The aqueous layer was extracted twice EtOAc andthe combined organics was washed with brine, dried, filtered, andevaporated to give a crude product. The product was purified by Gilsonand then lyophilized to produce1-{4-[4-(4-aminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,0.268 g (83%). Analysis: LCMS m/z=376 (M+1); ¹H NMR (400 MHz, DMSO-d₆)δ: 13.99 (br. s., 1H) 9.00 (br. s., 1H) 8.62 (d, J=8.28 Hz, 1H) 8.46(br. s., 1H) 7.83-8.03 (m, 3H) 7.71 (ddd, J=8.34, 6.84, 1.38 Hz, 1H)7.40-7.49 (m, 2H) 7.19 (d, J=8.78 Hz, 2H) 4.72 (dt, J=7.72, 4.05 Hz, 1H)3.85-3.96 (m, 1H) 3.73 (d, J=14.31 Hz, 1H) 3.22-3.43 (m, 2H) 2.36 (q,J=7.53 Hz, 2H) 1.89-2.08 (m, 2H) 1.47-1.72 (m, 2H) 1.01 (t, J=7.40 Hz,3H).

Example 232.1-{4-[4-(4-Dimethylaminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1. 3-Bromoquinolin-4-yl)-dimethylamine

A 50 mL pressure reaction vessel charged with 3-bromo-4-chloroquinoline(0.545 g, 2.25 mmol), dimethylamine (9 mL, 200 mmol, 2M solution inTHF), K₂CO₃ (1.5 g, 11 mmol), and acetonitrile (5 mL, 100 mmol) washeated at 135° C. and monitored by HPLC and LCMS. After 24 h, thereaction mixture was concentrated and then partitioned between EtOAc andsaturated aqueous NaHCO₃. The aqueous layer was extracted twice EtOAcand the combined organics was washed with brine, dried, filtered, andevaporated to give a crude product. The product was purified by Gilsonand then lyophilized to produce (3-bromoquinolin-4-yl)-dimethylamine,0.4 g (70%). Analysis: LCMS m/z=251 (M+1); ¹H NMR (400 MHz, CDCl₃) δ:8.80 (s, 1H) 8.12 (dd, J=8.53, 0.75 Hz, 1H) 8.00-8.06 (m, 1H) 7.63-7.71(m, 1H) 7.49-7.57 (m, 1H) 3.14 (s, 7H).

Step 2.1-{4-[4-(4-Dimethylaminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

This example was synthesized using 3-bromoquinolin-4-yl)-dimethylamineusing the methods described for Example 231. Analysis: LCMS m/z=404(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.66 (s, 1H) 8.42 (d, J=8.28 Hz, 1H)7.95-8.07 (m, 2H) 7.76 (dd, J=8.53, 1.51 Hz, 1H) 7.33-7.41 (m, 2H)7.12-7.19 (m, 2H) 4.72 (dt, J=7.84, 3.98 Hz, 1H) 3.85-3.96 (m, 3H) 3.71(br. s., 2H) 3.20-3.41 (m, 2H) 3.04 (s, 6H) 2.35 (q, J=7.53 Hz, 2H)1.89-2.07 (m, 2H) 1.55 (br. s., 2H) 1.00 (t, J=7.40 Hz, 3H).

The following examples were prepared using the methods described forExamples 231 and 232.

Example 233.{4-[4-(4-Dimethylaminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=446 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.66 (s, 1H)8.42 (d, J=8.53 Hz, 1H) 7.94-8.07 (m, 2H) 7.76 (ddd, J=8.66, 6.90, 1.51Hz, 1H) 7.37 (d, J=8.78 Hz, 2H) 7.16 (d, J=8.53 Hz, 2H) 4.65-4.78 (m,3H) 3.70-3.98 (m, 4H) 3.19-3.52 (m, 2H) 3.04 (s, 6H) 1.75-2.13 (m, 6H)1.46-1.72 (m, 2H).

Example 234.{4-[4-(4-Aminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone

Analysis: LCMS m/z=418 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 13.98 (br.s., 1H) 8.92-9.08 (m, 1H) 8.62 (d, J=8.53 Hz, 1H) 8.46 (br. s., 1H) 7.94(td, J=8.28, 7.03 Hz, 3H) 7.71 (ddd, J=8.34, 6.84, 1.38 Hz, 1H) 7.45 (d,J=8.53 Hz, 2H) 7.19 (d, J=8.53 Hz, 2H) 4.71 (d, J=7.78 Hz, 2H) 3.69-3.98(m, 6H) 3.21-3.53 (m, 3H) 1.90-2.13 (m, 4H) 1.77-1.90 (m, 2H) 1.47-1.74(m, 2H).

Example 235.1-{4-[4-(4-Methylaminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

A dried 50 mL R. B. flask under an atmosphere of argon was charged with1-{4-[4-(4-chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one(0.15 g, 0.38 mmol), methylamine (0.253 mL, 5.70 mmol), palladiumacetate (9.9 mg, 0.044 mmol), bis(2-diphenyl-phosphinophenyl)ether(0.047 g, 0.088 mmol), sodium tert-butoxide (0.0730 g, 0.760 mmol), and1,4-dioxane (2 mL). The reaction mixture was purged with argon andstirred at 85° C. overnight. The reaction mixture was cooled to RT andthe solvent was evaporated in vacuo. The residue was dissolved in EtOAcand washed with brine, dried, filtered, and concentrated. The crudeproduct was purified by Gilson and then lyophilized to produce1-{4-[4-(4-Methylaminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one.TFA,130 mg (68%). Analysis: LCMS m/z=390 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ:13.98 (br. s., 1H) 8.80 (br. s., 1H) 8.52 (d, J=8.53 Hz, 1H) 8.45 (s,1H) 7.89-8.00 (m, 2H) 7.74 (ddd, J=8.41, 6.53, 1.63 Hz, 1H) 7.37-7.45(m, 2H) 7.11 (d, J=8.78 Hz, 2H) 4.71 (dt, J=7.84, 3.98 Hz, 1H) 3.85-3.96(m, 2H) 3.66-3.78 (m, 1H) 3.30-3.41 (m, 1H) 3.20-3.30 (m, 1H) 2.65 (br.s., 3H) 2.35 (q, J=7.28 Hz, 2H) 1.99 (br. s., 2H) 1.46-1.70 (m, 2H) 1.00(t, J=7.40 Hz, 3H).

Example 236.{4-[4-(4-Methylaminoquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

A dried 50 mL R. B. flask under an atmosphere of argon was added{4-[4-(4-chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone(0.16 g, 0.38 mmol), methylamine (0.253 mL, 5.70 mmol), palladiumacetate (9.9 mg, 0.044 mmol), bis(2-diphenylphosphinophenyl)ether (0.047g, 0.088 mmol), sodium t-butoxide (0.0730 g, 0.760 mmol) and 1,4-dioxane(2 mL). The reaction mixture was purged with argon and stirred at 85° C.overnight, cooled to RT and concentrated. The crude product wasdissolved in EtOAc, washed with brine and dried to obtain a crudeproduct. The product was purified by Gilson and then lyophilized toproduce{4-[4-(4-methylamino-quinolin-3-yl)-phenoxy]-piperidin-l-yl}-(R)-tetrahydrofuran-2-yl-methanone.TFA,47 mg (24%). Analysis: LCMS m/z=432 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ:13.92 (br. s., 1H) 8.79 (br. s., 1H) 8.52 (d, J=8.53 Hz, 1H) 8.45 (br.s., 1H) 7.88-8.00 (m, 2H) 7.71-7.78 (m, 1H) 7.41 (d, J=8.53 Hz, 2H) 7.11(d, J=8.78 Hz, 2H) 4.65-4.77 (m, 2H) 3.70-3.81 (m, 6H) 3.19-3.51 (m, 4H)2.58-2.73 (m, 3H) 1.90-2.12 (m, 5H) 1.77-1.89 (m, 2H) 1.46-1.72 (m, 2H).

The following compounds were synthesized using the procedure asdescribed in Examples 235 and 236.

Example 237.1-{4-[4-(4-Morpholin-4-yl-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=446 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.77 (s, 1H)8.30 (d, J=8.03 Hz, 1H) 8.05-8.13 (m, 1H) 7.99 (t, J=7.28 Hz, 1H) 7.80(t, J=7.78 Hz, 1H) 7.39 (d, J=8.53 Hz, 2H) 7.18 (d, J=8.78 Hz, 2H)4.68-4.78 (m, 1H) 3.86-3.98 (m, 2H) 3.67-3.79 (m, 6H) 3.14-3.41 (m, 7H)2.36 (q, J=7.36 Hz, 2H) 1.90-2.08 (m, 2H) 1.47-1.71 (m, 2H) 1.00 (t,J=7.40 Hz, 3H).

Example 238.{4-[4-(4-Morpholin-4-yl-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=488 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.76 (s, 1H)8.30 (d, J=8.28 Hz, 1H) 8.09 (d, J=7.78 Hz, 1H) 7.99 (t, J=7.65 Hz, 1H)7.77-7.83 (m, 1H) 7.40 (d, J=8.53 Hz, 2H) 7.18 (d, J=8.53 Hz, 2H)4.66-4.80 (m, 2H) 3.70-3.97 (m, 12H) 3.17-3.24 (m, 6H) 1.91-2.12 (m, 5H)1.77-1.91 (m, 2H) 1.47-1.72 (m, 2H).

Example 239.1-(4-{4-[4-(4-Methylpiperazin-1-yl)-quinolin-3-yl]-phenoxy}-piperidin-1-yl)-propan-1-one

Analysis: LCMS m/z=459 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 10.03 (br.s., 1H) 8.77 (s, 1H) 8.23 (d, J=8.28 Hz, 1H) 8.11 (d, J=8.03 Hz, 1H)7.93 (t, J=7.28 Hz, 1H) 7.74-7.83 (m, 1H) 7.36 (d, J=8.53 Hz, 2H) 7.16(d, J=8.53 Hz, 2H) 4.63-4.77 (m, 1H) 3.84 (br. s., 28H) 3.20-3.49 (m,10H) 2.95-3.12 (m, 2H) 2.85 (s, 3H) 2.36 (q, J=7.28 Hz, 2H) 1.90-2.08(m, 2H) 1.48-1.72 (m, 2H) 1.01 (t, J=7.40 Hz, 3H).

Example 240.(4-{4-[4-(4-Methylpiperazin-1-yl)-quinolin-3-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=501 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.59 (br. s.,1H) 8.73 (s, 1H) 8.21 (d, J=8.28 Hz, 1H) 8.09 (d, J=8.53 Hz, 1H) 7.88(t, J=7.53 Hz, 1H) 7.75 (t, J=7.28 Hz, 1H) 7.36 (d, J=8.78 Hz, 2H) 7.17(d, J=8.53 Hz, 2H) 4.64-4.78 (m, 2H) 3.69-3.91 (m, 22H) 3.26-3.51 (m,11H) 2.90-3.04 (m, 3H) 2.84 (br. s., 3H) 1.91-2.13 (m, 5H) 1.85 (s, 3H)1.48-1.73 (m, 3H).

Example 241.3-[4-(4-Quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-oxazolidin-2-one

To a stirred solution of oxazolidin-2-one (0.2 g, 2 mmol) in toluene (5mL) was added sodium hydride (0.11 g, 4.6 mmol) under argon and thenheated at 60° C. for 15 h. Triphosgene (0.34 g, 1.1 mmol) was added tothe reaction mixture at −20° C. and slowly warmed to rt. Triethylamine(1 mL, 7 mmol) and 3-[4-(piperidin-4-yloxy)-phenyl]-quinoline (0.15 g,0.49 mmol) were added at 0° C., then warmed to rt and the reactionmonitored by HPLC and LCMS. After 2 h, the reaction mixture was quenchedwith saturated aqueous NaHCO₃, extracted twice with EtOAc and thecombined organics washed with brine, dried, filtered, and evaporated togive a crude product. The product was purified by Gilson and thenlyophilized to produce3-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-oxazolidin-2-one.TFA,0.103 g (39%). Analysis: LCMS m/z=418 (M+1); ¹H NMR (400 MHz, DMSO-d₆)δ: 9.34 (d, J=2.26 Hz, 1H) 8.75-8.85 (m, 1H) 8.10 (t, J=8.91 Hz, 2H)7.79-7.92 (m, 3H) 7.66-7.76 (m, 1H) 7.20 (d, J=8.78 Hz, 2H) 4.73-4.83(m, 1H) 4.39 (t, J=7.65 Hz, 2H) 3.85 (t, J=7.78 Hz, 2H) 3.66-3.78 (m,2H) 3.32-3.45 (m, 2H) 1.97-2.09 (m, 2H) 1.63-1.78 (m, 2H).

Example 242.1-[4-(4-Quinolin-3-yl-phenoxy)-piperidin-1-yl]-butane-1,3-dione

A 50 mL R. B. flask was charged with3-[4-(piperidin-4-yloxy)-phenyl]-quinoline (0.175 g, 0.575 mmol),acetonitrile (3 mL), 3-oxobutanoic acid ethyl ester (0.523 mL, 4.11mmol), and potassium carbonate (0.284 g, 2.05 mmol) and then heated at97° C. under an argon atmosphere for 8 h. The reaction mixture wasevaporated in vacuo, and partitioned between water and EtOAc. Theaqueous layer was acidified with citric acid to pH 5 then extractedtwice with EtOAc and the combined organics washed with brine, dried,filtered, and evaporated to give a crude product. The product waspurified by Gilson and then lyophilized to produce1-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-butane-1,3-dione, TFA,0.180 g (62%). Analysis: LCMS m/z=389 (M+1); ¹H NMR (400 MHz, DMSO-d₆)δ: 9.37 (d, J=2.26 Hz, 1H) 8.80-8.89 (m, 1H) 8.12 (dd, J=11.80, 8.28 Hz,2H) 7.82-7.93 (m, 3H) 7.70-7.78 (m, 1H) 7.15-7.25 (m, 2H) 4.70-4.82 (m,1H) 3.81-3.94 (m, 1H) 3.69 (s, 2H) 3.55-3.65 (m, 1H) 3.25-3.38 (m, 2H)2.17 (s, 3H) 1.88-2.05 (m, 3H) 1.50-1.72 (m, 2H).

Example 243.1-[4-(4-Quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-pyrrolidin-2-one

To a cold (0° C.) stirred solution of 2-pyrrolidinone (0.2 g, 2 mmol)and triethylamine (2 mL, 20 mmol) in 1,2-dichloroethane (5 mL) was addedtriphosgene (0.3 g, 1 mmol) and stirred at rt for 1.5 h.3-[4-(piperidin-4-yloxy)-phenyl]-quinoline (0.12 g, 0.39 mmol) and K₂CO₃were added to the reaction mixture at 0° C. and then stirred at rt for 4h. The reaction mixture was evaporated and partitioned between saturatedaqueous NaHCO₃ and EtOAc. The aqueous layer was extracted twice withEtOAc and the combined organics was washed with brine, dried, filtered,and evaporated to give a crude product. The product was purified byGilson and then lyophilized to produce1-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-pyrrolidin-2-one.TFA,0.125 g (61%). Analysis: LCMS m/z=416 (M+1); ¹H NMR (400 MHz, DMSO-d₆)δ: 9.34 (d, J=2.26 Hz, 1H) 8.80 (s, 1H) 8.10 (t, J=8.91 Hz, 2H)7.80-7.93 (m, 3H) 7.68-7.76 (m, 1H) 7.20 (d, J=8.78 Hz, 2H) 4.71-4.82(m, 1H) 3.61 (t, J=7.03 Hz, 4H) 3.54-3.80 (m, 4H) 3.26-3.42 (m, 2H) 2.40(t, J=7.91 Hz, 2H) 1.92-2.09 (m, 4H) 1.60-1.78 (m, 2H).

Example 244.4′-[1-((R)-Tetrahydrofuran-2-carbonyl)-piperidin-4-yloxy]-biphenyl-4-carbonitrile

Step 1. 4-(4′-Cyanobiphenyl-4-yloxy)-piperidine-1-carboxylic acidtert-butyl ester

A 50 mL R. B. flask charged with 1,4-dioxane (4.00 mL),triphenylphosphine (0.0607 g, 0.231 mmol), and palladium acetate (0.0130g, 0.0578 mmol) was stirred at rt for 15 min under an argon atmosphere.4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.6 g, 1 mmol), 4-bromobenzonitrile (0.210 g, 1.16mmol), DMF (4.00 mL), and 1M aqueous Na₂CO₃ (4 mL) were added andflushed with argon five times. The reaction mixture was heated at 80° C.for 7 h and concentrated. The residue was suspended in a mixture ofaqueous 1M Na₂CO₃ and EtOAc and then filtered through a pad ofcelite/silica gel. The filtrate was separated into two layers and theaqueous layer was extracted twice with EtOAc. The combined organics waswashed with brine, dried, filtered, and evaporated to give a crudeproduct that was purified by silica gel column chromatography (80 g ISCOcolumn, using 0 to 40% EtOAc in hexane) to give 0.5 g (90%). Analysis:LCMS m/z=379 (M+1); ¹H NMR (400 MHz, CHLOROFORM-d) δ: 7.60-7.74 (m, 4H),7.53 (d, J=8.8 Hz, 2H), 6.98-7.04 (m, 2H), 4.50-4.58 (m, 1H), 3.65-3.77(m, 2H), 3.32-3.42 (m, 2H), 1.89-2.01 (m, 2H), 1.73-1.84 (m, 2H),1.44-1.51 (m, 11H).

Step 2. 4′-(Piperidin-4-yloxy)-biphenyl-4-carbonitrile

To a solution of 4-(4′-cyan-biphenyl-4-yloxy)-piperidine-1-carboxylicacid tert-butyl ester (0.5 g, 1 mmol) in DCM (7 mL) was added TFA (0.51mL, 6.6 mmol) at RT. The reaction mixture was stirred 3 h and was thenconcentrated. This material was used directly in the next step.Analysis: LCMS m/z=279 (M+1).

Step 3.4′-[1-((R)-Tetrahydrofuran-2-carbonyl)-piperidin-4-yloxy]-biphenyl-4-carbonitrile

To a cold (5° C.) stirred solution of (R)-tetrahydrofuran-2-carboxylicacid (0.250 g, 2.16 mmol) and triethylamine (2.00 mL, 14.4 mmol) in DCM(5 mL) was added HATU (0.765 g, 2.01 mmol). After 15 min4′-(piperidin-4-yloxy)-biphenyl-4-carbonitrile (0.4 g, 1 mmol) was addedand further stirred at rt for 2 h. The reaction mixture was concentratedand then partitioned between EtOAc and saturated aqueous NaHCO₃. Theaqueous layer was extracted twice with EtOAc and the combined organicswas washed with brine, dried, filtered, and concentrated. The productwas purified by Gilson and then lyophilized to produce4′-[1-((R)-tetrahydrofuran-2-carbonyl)-piperidin-4-yloxy]-biphenyl-4-carbonitrile,0.313 g (overall 58%). Analysis: LCMS m/z=377 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ: 7.81-7.91 (m, 2H) 7.71 (d, J=8.78 Hz, 1H) 7.12 (d, J=8.53Hz, 1 H) 4.65-4.77 (m, 1H) 3.76 (d, J=6.78 Hz, 2H) 3.18-3.51 (m, 2H)1.74-2.11 (m, 3H) 1.44-1.70 (m, 1H).

The following compounds were synthesized using the procedures ofExamples 1-7.

Example 245.1-[4-(4-Benzofuran-2-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=350 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.76-7.83 (m,2H), 7.47-7.58 (m, 2H), 7.18-7.26 (m, 2H), 6.96-7.02 (m, 2H), 6.90 (s,1H), 4.61 (tt, J=6.59, 3.33 Hz, 1H), 3.76-3.86 (m, 1H), 3.61-3.75 (m,2H), 3.38-3.49 (m, 1H), 2.38 (q, J=7.36 Hz, 2H), 1.77-2.02 (m, 4H), 1.17(t, J=7.40 Hz, 3H).

Example 246.1-{4-[4-(1H-Indol-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=349 (M+1); ¹H NMR (400 MHz, CD₃OD): δ:7.81 (d, J=7.78Hz, 1H), 7.58 (d, J=8.28 Hz, 2H), 7.34-7.43 (m, 2H), 7.11-7.18 (m, 1H),7.02-7.09 (m, 3H), 4.65 (tt, J=6.93, 3.48 Hz, 1H), 3.75-3.92 (m, 2H),3.46-3.63 (m, 2H), 2.42-2.51 (m, 2H), 1.96-2.09 (m, 2H), 1.73-1.89 (m,2H), 1.13-1.18 (m, 3H).

Example 247.1-[4-(4-Benzo[b]thiophen-5-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=366 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.97 (d, J=1.51Hz, 1H), 7.91 (d, J=8.53 Hz, 1H), 7.51-7.62 (m, 3H), 7.45-7.50 (m, 1H),7.37 (d, J=5.52 Hz, 1H), 6.97-7.07 (m, 2H), 4.60 (tt, J=6.65, 3.26 Hz,1H), 3.79-3.87 (m, 1H), 3.63-3.77 (m, 2H), 3.39-3.49 (m, 1H), 2.34-2.45(m, 2H), 1.80-2.03 (m, 4H), 1.17 (t, J=7.53 Hz, 3H).

Example 248.1-{4-[4-(1H-Indazol-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=350 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 10.07 (br. s.,1H), 8.01 (d, J=8.28 Hz, 1H), 7.91 (d, J=8.78 Hz, 1H), 7.39-7.57 (m,2H), 7.19-7.34 (m, 4H), 7.06 (d, J=8.78 Hz, 2H), 4.63 (tt, J=6.59, 3.45Hz, 1H), 3.58-3.94 (m, 3H), 3.32-3.55 (m, 1H), 2.39 (q, J=7.53 Hz, 2H),1.74-2.12 (m, 4H), 1.18 (t, J=7.53 Hz, 3H).

Example 249.1-{4-[4-(1-Methyl-1H-indazol-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,TFA salt

Analysis: LCMS m/z=364 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.01 (d, J=0.75Hz, 1H), 7.74-7.81 (m, 1H), 7.61 (d, J=8.78 Hz, 2H), 7.50 (s, 1H), 7.38(dd, J=8.53, 1.25 Hz, 1H), 6.99-7.06 (m, 2H), 4.60-4.69 (m, 1H), 4.12(s, 3H), 3.67-3.83 (m, 3H), 3.43-3.57 (m, 1H), 2.42-2.47 (m, 2H),1.87-2.04 (m, 4H), 1.19 (t, J=7.53 Hz, 3H).

Example 250.1-[4-(4-Thieno[2,3-b]pyridin-5-yl-phenoxy)-piperidin-1-yl]-propan-1-one,TFA salt

Analysis: LCMS m/z=367 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.85 (d, J=1.76Hz, 1H), 8.31 (d, J=2.01 Hz, 1H), 7.63 (d, J=5.77 Hz, 1H), 7.55-7.60 (m,2H), 7.36 (d, J=6.02 Hz, 1H), 7.01-7.10 (m, 2H), 4.63-4.69 (m, 1H), 3.76(br. s., 3H), 3.50 (br. s., 1H), 2.43 (q, J=7.36 Hz, 2H), 1.82-2.05 (m,4H), 1.19 (t, J=7.53 Hz, 3H).

Example 251.1-{4-[4-(2-Methyl-2H-indazol-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=364 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.97 (s, 1H),7.89 (d, J=1.25 Hz, 1H), 7.74 (dd, J=8.78, 1.00 Hz, 1H), 7.56-7.66 (m,2H), 7.45 (dd, J=8.78, 1.51 Hz, 1H), 6.98-7.05 (m, 2H), 4.60-4.71 (m,1H), 4.33 (s, 3H), 3.69-3.89 (m, 3H), 3.46-3.59 (m, 1H), 2.46 (q, J=7.53Hz, 2H), 1.86-1.98 (m, 4H), 1.20 (t, J=7.53 Hz, 3H).

Example 252.1-[4-(4-[1,8]Naphthyridin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one,TFA salt

Analysis: LCMS m/z=362 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.57 (d, J=2.26Hz, 1H), 9.32 (dd, J=4.52, 1.51 Hz, 1H), 8.48-8.59 (m, 2H), 7.78 (dd,J=8.28, 4.52 Hz, 1H), 7.66-7.73 (m, 2H), 7.07-7.16 (m, 2H), 4.62-4.76(m, 1H), 3.77 (br. s., 3H), 3.43-3.62 (m, 1H), 2.44 (q, J=7.53 Hz, 2H),1.84-2.09 (m, 4H), 1.19 (t, J=7.53 Hz, 3H).

Example 253.1-{4-[4-(2-Methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,TFA salt

Analysis: LCMS m/z=375 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.74 (d, J=1.00Hz, 1H), 8.57 (d, J=8.53 Hz, 1H), 8.03 (d, J=1.00 Hz, 2H), 7.73-7.81 (m,2H), 7.54 (d, J=8.53 Hz, 1H), 7.06-7.14 (m, 2H), 4.65 (tt, J=6.62, 3.42Hz, 1H), 3.67-3.90 (m, 3H), 3.42-3.53 (m, 1H), 3.07 (s, 3H), 2.40 (d,J=7.53 Hz, 2H), 1.84-2.07 (m, 4H), 1.18 (t, J=7.53 Hz, 3H).

Example 254.(R)-Tetrahydrofuran-2-yl-[4-(4-thieno[2,3-b]pyridin-5-yl-phenoxy)-piperidin-1-yl]-methanone,TFA salt

Analysis: LCMS m/z=409 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.85 (d, J=2.01Hz, 1H), 8.32 (d, J=2.01 Hz, 1H), 7.63 (d, J=5.77 Hz, 1H), 7.58 (d,J=8.53 Hz, 2H), 7.37 (d, J=6.02 Hz, 1H), 7.02-7.10 (m, 2H), 4.61-4.72(m, 2H), 3.47-4.05 (m, 6H), 1.80-2.16 (m, 8H).

Example 255.Cyclopropyl-[4-(4-thieno[2,3-b]pyridin-5-yl-phenoxy)-piperidin-1-yl]-methanone,TFA salt

Analysis: LCMS m/z=379 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.82 (d, J=2.26Hz, 1H), 8.27 (d, J=2.26 Hz, 1H), 7.55-7.64 (m, 3H), 7.34 (d, J=5.77 Hz,1H), 7.04-7.11 (m, 2H), 4.65 (tt, J=6.56, 3.36 Hz, 1H), 3.75-4.03 (m,2H), 3.70 (ddd, J=13.49, 6.84, 4.02 Hz, 2H), 1.84-2.09 (m, 4H), 1.79(tt, J=8.00, 4.67 Hz, 1H), 0.98-1.05 (m, 2H), 0.79 (dd, J=8.03, 3.01 Hz,2H).

Example 256.1-[4-(4-Imidazo[1,2-a]pyridin-6-yl-phenoxy)-piperidin-1-yl]-propan-1-one,TFA salt

Analysis: LCMS m/z=350 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.34-8.45 (m,2H), 7.89-8.01 (m, 2H), 7.75 (d, J=1.76 Hz, 1H), 7.51 (d, J=8.78 Hz,2H), 7.07 (d, J=8.78 Hz, 2H), 4.65 (tt, J=6.46, 3.33 Hz, 1H), 3.74 (br.s., 4H), 3.48-3.57 (m, 1H), 2.38-2.49 (m, 2H), 1.82-2.07 (m, 4H), 1.18(t, J=7.40 Hz, 3H).

Example 257.{4-[4-(4-Chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone,TFA salt

Analysis: LCMS m/z=437 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.04 (d, J=5.52Hz, 1H), 8.56 (s, 1H), 8.40 (d, J=9.03 Hz, 1H), 8.06-8.16 (m, 1H),7.72-7.82 (m, 3H), 7.09 (d, J=8.78 Hz, 2H), 4.63-4.73 (m, 2H), 3.51-4.02(m, 6H), 1.91-2.13 (m, 8H).

Example 258.{4-[4-(4-Chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-cyclopropyl-methanone,TFA salt

Analysis: LCMS m/z=407 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.05 (d, J=5.52Hz, 1H), 8.57 (d, J=1.51 Hz, 1H), 8.40 (d, J=8.78 Hz, 1H), 8.10 (dd,J=9.03, 1.76 Hz, 1H), 7.72-7.81 (m, 3H), 7.06-7.15 (m, 2H), 4.62-4.75(m, 1H), 3.76-4.02 (m, 2H), 3.67-3.76 (m, 2H), 1.87-2.13 (m, 4H),1.75-1.85 (m, 1H), 1.02 (dd, J=4.52, 2.76 Hz, 2H), 0.80 (dd, J=8.03,3.01 Hz, 2H).

Example 259.1-{4-[4-(4-Chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,TFA salt

Analysis: LCMS m/z=395 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.03 (d, J=5.52Hz, 1H), 8.55 (d, J=1.51 Hz, 1H), 8.39 (d, J=8.78 Hz, 1H), 8.08 (dd,J=8.78, 1.76 Hz, 1H), 7.67-7.80 (m, 3H), 7.09 (d, J=8.78 Hz, 2H),4.61-4.73 (m, 1H), 3.54-3.92 (m, 4H), 2.41 (d, J=7.53 Hz, 2H), 1.83-2.06(m, 4H), 1.18 (t, J=7.53 Hz, 3H).

Example 260.{4-[4-(8-Chloro-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone,TFA salt

Analysis: LCMS m/z=437 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.33 (d, J=4.52Hz, 1H), 8.51-8.58 (m, 1H), 7.93 (d, J=8.53 Hz, 1H), 7.70-7.79 (m, 2H),7.52 (d, J=8.53 Hz, 2H), 7.05 (d, J=8.78 Hz, 2H), 4.65-4.73 (m, 2H),3.53-4.03 (m, 6H), 1.89-2.31 (m, 8H).

Example 261.1-{4-[4-(8-Chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=395 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.10 (dd,J=4.14, 1.63 Hz, 1H), 8.22 (dd, J=8.28, 1.51 Hz, 1H), 7.79 (d, J=8.53Hz, 1H), 7.47-7.59 (m, 4H), 7.00-7.08 (m, 2H), 4.59-4.69 (m, 1H),3.80-3.91 (m, 1H), 3.64-3.78 (m, 2H), 3.40-3.51 (m, 1H), 2.33-2.45 (m,2H), 1.82-2.06 (m, 4H), 1.18 (t, J=7.53 Hz, 3H).

Example 262.{4-[4-(7-Methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone

Step 1. 4-[4-(7-Methoxyquinolin-3-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester

This compound was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and 3-bromo-7-methoxyquinoline(443 mg, 1.86 mmol) in an analogous manner to Example 378. Productisolated as a solid (0.46 g, 85%). Analysis: LCMS m/z=435 (M+1).

Step 2. 7-Methoxy-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline

This compound was prepared from4-[4-(7-methoxyquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester (0.46 g, 1.05 mmol) and TFA (2 mL) in an analogousmanner to Example 378. Product isolated as a solid (0.24 g, 68%).Analysis: LCMS m/z=335 (M+1).

Step 3.{4-[4-(7-Methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

This compound was prepared from7-methoxy-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline (90 mg, 0.3 mmol)and (R)-tetrahydrofuran-2-carboxylic acid (52 uL, 0.54 mmol) in ananalogous manner to Example 418. Product isolated as a solid (0.02 g,20%). Analysis: LCMS m/z=433 (M+1). ¹H NMR (DMSO-d6) δ: 9.14 (d, 1H,J=2.4 Hz), 8.49 (d, 1H, J=2.3 Hz), 7.94 (d, 1H, J=9.0 Hz), 7.79 (m, 2H),7.41 (d, 1H, J=2.4 Hz), 7.29 (m, 1H), 7.15 (m, 2H), 4.72 (m, 2H), 3.93(s, 3H), 3.77 (br m, 4H), 3.36 (m, 1H), 3.29 (m, 1H), 2.06 (br m, 4H),1.84 (m, 2H), 1.60 (m, 2H).

Example 263.(R)-Tetrahydrofuran-2-yl-[4-(4-thieno[3,2-b]pyridin-6-yl-phenoxy)-piperidin-1-yl]-methanone,TFA salt

Analysis: LCMS m/z=409 (M+1); ¹H NMR (400 MHz, CDCl₃) δ; 9.10 (d, J=1.76Hz, 1H), 8.71 (d, J=1.25 Hz, 1H), 8.05 (d, J=5.77 Hz, 1H), 7.94 (d,J=5.52 Hz, 1H), 7.62 (d, J=8.53 Hz, 2H), 7.06-7.14 (m, 2H), 4.66 (dd,J=7.40, 5.65 Hz, 2H), 3.64-4.01 (m, 6H), 2.24-2.38 (m, 1H), 1.86-2.16(m, 7H).

Example 264.1-[4-(4-Thieno[3,2-b]pyridin-6-yl-phenoxy)-piperidin-1-yl]-propan-1-one,TFA salt

Analysis: LCMS m/z=367 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.11 (d, J=1.76Hz, 1H), 8.73 (s, 1H), 8.06 (s, 1H), 7.92-8.00 (m, 1H), 7.62 (d, J=8.78Hz, 2H), 7.08 (d, J=8.78 Hz, 2H), 4.59-4.73 (m, 1H), 3.75-3.84 (m, 2H),3.49-3.59 (m, 2H), 2.38-2.50 (m, 2H), 1.86-2.06 (m, 4H), 1.19 (t, J=7.40Hz, 3H).

Example 265.{4-[4-(3-Chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone,TFA salt

Analysis: LCMS m/z=437 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.93 (d, J=2.26Hz, 1H), 8.34 (d, J=0.75 Hz, 1H), 8.27 (d, J=1.76 Hz, 1H), 7.83-7.93 (m,2H), 7.70 (d, J=8.78 Hz, 2H), 7.06 (d, J=8.78 Hz, 2H), 4.66 (dd, J=7.40,5.65 Hz, 2H), 3.46-4.01 (m, 6H), 2.28-2.34 (m, 1H), 1.87-2.15 (m, 7H).

Example 266.1-{4-[4-(3-Chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,TFA salt

Analysis: LCMS m/z=395 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.94 (d, J=2.26Hz, 1H), 8.35 (s, 1H), 8.29 (d, J=2.26 Hz, 1H), 7.82-7.94 (m, 2H), 7.70(d, J=8.78 Hz, 2H), 7.06 (d, J=8.78 Hz, 2H), 4.61-4.72 (m, 1H),3.64-3.88 (m, 3H), 3.41-3.56 (m, 1H), 2.39-2.48 (m, 2H), 1.85-2.03 (m,4H), 1.18-1.23 (m, 3H).

Example 267.[4-(4-Benzothiazol-5-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydrofuran-2-yl-methanone,TFA salt

Analysis: LCMS m/z=409 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.15 (s, 1H),8.33 (d, J=1.25 Hz, 1H), 8.01 (d, J=8.28 Hz, 1H), 7.67-7.74 (m, 1H),7.62 (d, J=8.53 Hz, 2H), 7.04 (d, J=8.78 Hz, 2H), 4.62-4.73 (m, 2H),3.62-4.06 (m, 6H), 1.87-2.31 (m, 8H).

Example 268.[4-(4-Benzothiazol-5-yl-phenoxy)-piperidin-1-yl]-cyclopropylmethanone,TFA salt

Analysis: LCMS m/z=379 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.19 (s, 1H),8.32-8.37 (m, 1H), 7.97-8.07 (m, 1H), 7.68-7.75 (m, 1H), 7.63 (d, J=8.78Hz, 2H), 7.05 (d, J=8.78 Hz, 2H), 4.61-4.71 (m, 1H), 3.73-3.81 (m, 4H),1.88-2.10 (m, 4H), 1.78-1.86 (m, 1H), 1.02-1.08 (m, 2H), 0.79-0.88 (m,2H).

Example 269.1-[4-(4-Benzothiazol-5-yl-phenoxy)-piperidin-1-yl]-propan-1-one; TFAsalt

Analysis: LCMS m/z=367 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.15-9.21 (m,1H), 8.33 (d, J=1.25 Hz, 1H), 8.01 (d, J=8.28 Hz, 1H), 7.71 (dd, J=8.28,1.51 Hz, 1H), 7.59-7.66 (m, 2H), 7.00-7.10 (m, 2H), 4.65 (br. s., 1H),3.71-3.88 (m, 3H), 3.48-3.61 (m, 1H), 2.46 (d, J=7.53 Hz, 2H), 1.95 (br.s., 4H), 1.20 (t, J=7.53 Hz, 3H).

Example 270.Cyclopropyl-{4-[4-(1-methyl-1H-indazol-6-yl)-phenoxy]-piperidin-1-yl})-methanone.TFA salt

Analysis: LCMS m/z=376 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.05 (1H, s),7.79 (1H, d, J=8.5 Hz), 7.57-7.64 (2H, m), 7.51 (1H, s), 7.37-7.43 (1H,m), 7.04 (2H, d, J=8.8 Hz), 4.63-4.71 (1H, m), 3.78 (4H, br. s.),1.87-2.07 (4H, m), 1.76-1.85 (1H, m), 0.99-1.10 (2H, m), 0.75-0.87 (2H,m).

Example 271.Cyclobutyl-{4-[4-(1-methyl-1H-indazol-6-yl)-phenoxy]-piperidin-1-yl}-methanone,TFA salt

Analysis: LCMS m/z=390 (M+1); ¹H NMR (400 MHz, CD₃OD): δ: 8.37 (1H, d,J=1.0 Hz), 8.17 (1H, dd, J=8.5, 0.8 Hz), 8.02-8.11 (3H, m), 7.81 (1H,dd, J=8.5, 1.5 Hz), 7.39-7.52 (2H, m), 5.08 (1H, dt, J=7.0, 3.5 Hz),4.24 (1H, td, J=8.7, 4.0 Hz), 4.03-4.15 (1H, m), 3.80-4.00 (3H, m),2.54-2.77 (4H, m), 2.05-2.50 (6H, m).

Example 272.{4-[4-(8-Methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone,TFA salt

Analysis: LCMS m/z=433 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.49 (dd,J=5.27, 1.51 Hz, 1H), 8.66-8.78 (m, 1H), 7.85 (s, 3H), 7.72 (d, J=8.78Hz, 2H), 7.07 (d, J=9.04 Hz, 2H), 4.62-4.73 (m, 2H), 3.54-4.03 (m, 9H),2.26-2.37 (m, 1H), 1.89-2.00 (m, 7H).

Example 273.1-{4-[4-(8-Methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,TFA

salt.

Analysis: LCMS m/z=433 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.42-9.52 (m,1H), 8.79 (dd, J=8.41, 1.13 Hz, 1H), 7.85-7.93 (m, 3H), 7.67-7.76 (m,2H), 7.04-7.12 (m, 2H), 4.64-4.73 (m, 1H), 3.73-3.86 (m, 3H), 3.70 (s,3H), 3.45-3.59 (m, 1H), 2.37-2.50 (m, 2H), 1.82-2.08 (m, 4H), 1.19 (t,J=7.53 Hz, 3H).

Example 274.Cyclopropyl-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone,HCl

Analysis: LCMS m/z=403 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.40 (d, J=4.52Hz, 1H), 8.84 (d, J=7.78 Hz, 1H), 7.87-7.98 (m, 3H), 7.72-7.80 (m, 2H),7.09 (d, J=8.78 Hz, 2H), 4.62-4.76 (m, 1H), 3.87 (s, 5H), 3.66-3.76 (m,2H), 1.99-2.13 (m, 2H), 1.91 (br. s., 2H), 1.74-1.84 (m, 1H), 0.96-1.04(m, 2H), 0.74-0.83 (m, 2H).

Example 275.{4-[4-(6-Methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone

Analysis: LCMS m/z=417 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.87 (dd,J=4.27, 1.76 Hz, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.68 (s, 1H),7.33-7.40 (m, 3H), 7.01 (d, J=8.78 Hz, 2H), 4.66 (dd, J=7.15, 5.65 Hz,2H), 3.49-4.01 (m, 6H), 2.44 (s, 3H), 2.28-2.37 (m, 1H), 1.85-2.11 (m,7H).

Example 276.1-{4-[4-(6-Methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=375 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.87 (dd,J=4.27, 1.76 Hz, 1H), 8.07-8.14 (m, 1H), 7.95 (s, 1H), 7.68 (s, 1H),7.35 (d, J=8.78 Hz, 3H), 7.00 (d, J=8.78 Hz, 2H), 4.59-4.67 (m, 1H),3.81-3.90 (m, 1H), 3.62-3.79 (m, 2H), 3.41-3.51 (m, 1H), 2.44 (s, 3H),2.36-2.43 (m, 2H), 1.94-2.04 (m, 2H), 1.83-1.93 (m, 2H), 1.18 (t, J=7.53Hz, 3H).

Example 277.7-[4-(1-Propionyl-piperidin-4-yloxy)-phenyl]-quinoline-3-carbonitrile

Analysis: LCMS m/z=386 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.04 (d, J=2.26Hz, 1H), 8.53 (d, J=1.25 Hz, 1H), 8.32 (d, J=1.00 Hz, 1H), 7.93 (d,J=1.00 Hz, 2H), 7.72 (d, J=8.78 Hz, 2H), 7.07 (d, J=8.78 Hz, 2H),4.59-4.71 (m, 1H), 3.79-3.88 (m, 1H), 3.65-3.77 (m, 2H), 3.39-3.51 (m,1H), 2.39 (d, J=7.53 Hz, 2H), 1.96-2.03 (m, 2H), 1.82-1.94 (m, 2H), 1.18(t, J=7.53 Hz, 3H).

Example 278.7-{4-[1-((R)-Tetrahydrofuran-2-carbonyl)-piperidin-4-yloxy]-phenyl}-quinoline-3-carbonitrile

Analysis: LCMS m/z=428 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.04 (d, J=2.01Hz, 1H), 8.53 (dd, J=2.26, 0.75 Hz, 1H), 8.32 (d, J=1.00 Hz, 1H), 7.94(d, J=1.26 Hz, 2H), 7.72 (d, J=8.78 Hz, 2H), 7.07 (d, J=8.78 Hz, 2H),4.65 (dd, J=7.28, 5.52 Hz, 2H), 3.54-4.02 (m, 6H), 2.29-2.40 (m, 1H),1.87-2.13 (m, 7H).

Example 279.7-[4-(1-Cyclopropanecarbonyl-piperidin-4-yloxy)-phenyl]-quinoline-3-carbonitrile

Analysis: LCMS m/z=398 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.04 (d, J=2.01Hz, 1H), 8.53 (dd, J=2.26, 0.75 Hz, 1H), 8.33 (d, J=0.75 Hz, 1H), 7.94(d, J=1.00 Hz, 2H), 7.72 (d, J=8.78 Hz, 2H), 7.08 (d, J=9.03 Hz, 2H),4.61-4.72 (m, 1H), 3.77-4.05 (m, 2H), 3.65-3.76 (m, 2H), 2.01 (s, 4H),1.79 (s, 1H), 0.97-1.05 (m, 2H), 0.78 (dd, J=8.03, 3.01 Hz, 2H).

Example 280.1-{4-[4-(3-Methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=375 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.78 (d, J=2.01Hz, 1H), 8.23 (s, 1H), 7.90-7.98 (m, 1H), 7.73-7.83 (m, 2H), 7.69 (d,J=8.78 Hz, 2H), 7.04 (d, J=8.78 Hz, 2H), 4.62 (tt, J=6.56, 3.36 Hz, 1H),3.83 (br. s., 1H), 3.63-3.77 (m, 2H), 3.45 (dd, J=6.90, 4.39 Hz, 1H),2.53 (s, 3H), 2.39 (d, J=7.03 Hz, 2H), 1.93-2.04 (m, 2H), 1.81-1.92 (m,2H), 1.18 (t, J=7.53 Hz, 3H).

Example 281.{4-[4-(3-Methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone

Analysis: LCMS m/z=417 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.78 (d, J=2.01Hz, 1H), 8.21-8.25 (m, 1H), 7.90-7.96 (m, 1H), 7.73-7.83 (m, 2H),7.67-7.71 (m, 2H), 7.04 (d, J=9.04 Hz, 2H), 4.72-4.79 (m, 1H), 3.37-3.68(m, 4H), 3.13 (s, 2H), 3.07 (s, 5H), 2.53 (s, 3H), 2.15-2.27 (m, 2H),2.03 (br. s., 2H).

Example 282.Cyclopropyl-{4-[4-(3-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=387 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.78 (d, J=2.26Hz, 1H), 8.24 (s, 1H), 7.91-7.96 (m, 1H), 7.74-7.83 (m, 2H), 7.69 (d,J=8.78 Hz, 2H), 7.05 (d, J=8.78 Hz, 2H), 4.61-4.69 (m, 1H), 3.79-4.01(m, 2H), 3.63-3.73 (m, 2H), 2.53 (s, 3H), 1.84-2.12 (m, 4H), 1.79 (s,1H), 1.00 (dd, J=4.39, 2.89 Hz, 2H), 0.77 (dd, J=7.91, 3.14 Hz, 2H).

Example 283.{4-[4-(8-Methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=406 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.19 (d, J=0.75Hz, 1H), 7.76 (s, 1H), 7.66 (d, J=1.51 Hz, 1H), 7.49 (d, J=8.53 Hz, 2H),7.43 (br. s., 1H), 6.99-7.07 (m, 2H), 4.65 (dd, J=7.15, 5.65 Hz, 2H),3.50-4.01 (m, 6H), 2.81 (s, 3H), 2.27-2.39 (m, 1H), 1.90-2.11 (m, 7H).

Example 284.1-{4-[4-(8-Methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=364 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.13 (dd,J=1.51, 0.75 Hz, 1H), 7.62 (dd, J=10.79, 1.00 Hz, 2H), 7.48 (d, J=8.78Hz, 2H), 7.17-7.24 (m, 1H), 7.01 (d, J=8.78 Hz, 2H), 4.55-4.65 (m, 1H),3.60-3.88 (m, 3H), 3.39-3.51 (m, 1H), 2.67 (s, 3H), 2.39 (d, J=7.53 Hz,2H), 1.75-2.04 (m, 4H), 1.16-1.22 (m, 3H).

Example 285.{4-[4-(5-Methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=406 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.73 (d, J=1.25Hz, 1H), 7.52-7.61 (m, 2H), 7.28 (s, 2H), 7.18 (d, J=9.03 Hz, 1H), 7.00(d, J=8.78 Hz, 2H), 4.55-4.71 (m, 2H), 3.49-4.00 (m, 6H), 2.55 (s, 3H),2.26-2.40 (m, 1H), 2.01 (s, 7H).

Example 286.1-{4-[4-(5-Methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=364 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.73 (d, J=1.26Hz, 1H), 7.51-7.60 (m, 2H), 7.28 (s, 2H), 7.18 (d, J=9.29 Hz, 1H), 7.00(d, J=8.78 Hz, 2H), 4.56-4.66 (m, 1H), 3.64-3.90 (m, 3H), 3.41-3.49 (m,1H), 2.55 (s, 3H), 2.35-2.44 (m, 2H), 1.82-2.05 (m, 4H), 1.18 (t, J=7.53Hz, 3H).

Example 287.Cyclopropyl-{4-[4-(5-methyl-imidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl})-methanone

Analysis: LCMS m/z=376 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.73 (d, J=1.00Hz, 1H), 7.58 (d, J=9.04 Hz, 1H), 7.53 (s, 1H), 7.26-7.29 (m, 3H), 7.18(d, J=9.03 Hz, 1H), 6.98-7.05 (m, 2H), 4.58-4.67 (m, 1H), 3.79-4.03 (m,2H), 3.64-3.73 (m, 2H), 2.55 (s, 3H), 2.01 (s, 4H), 1.75-1.83 (m, 1H),1.01 (dd, J=4.39, 2.89 Hz, 2H), 0.78 (dd, J=7.91, 3.14 Hz, 2H).

Example 288.Cyclopropyl-{4-[4-(8-methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl})-methanone

Analysis: LCMS m/z=376 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.13 (d, J=0.75Hz, 1H), 7.62 (dd, J=10.04, 1.25 Hz, 2H), 7.45-7.52 (m, 2H), 7.20 (d,J=1.25 Hz, 1H), 6.99-7.06 (m, 2H), 4.58-4.67 (m, 1H), 3.75-4.00 (m, 2H),3.61-3.74 (m, 2H), 2.67 (s, 3H), 2.01 (s, 4H), 1.78 (s, 1H), 0.97-1.06(m, 2H), 0.78 (dd, J=8.03, 3.01 Hz, 2H).

Example 289.{4-[4-(2,3-Dimethylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran2-yl-methanone

Analysis: LCMS m/z=420 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.88 (s, 1H),7.55 (dd, J=9.29, 0.75 Hz, 1H), 7.50 (d, J=8.53 Hz, 2H), 7.33 (dd,J=9.29, 1.76 Hz, 1H), 6.98-7.04 (m, 2H), 4.55-4.69 (m, 2H), 3.95 (s,6H), 2.44 (d, J=3.51 Hz, 6H), 2.28-2.38 (m, 1H), 1.86-2.11 (m, 7H).

Example 290.1-{4-[4-(2,3-Dimethylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=378 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.88 (s, 1H),7.55 (d, J=9.29 Hz, 1H), 7.48-7.52 (m, 2H), 7.33 (dd, J=9.29, 1.76 Hz,1H), 6.98-7.05 (m, 2H), 4.55-4.66 (m, 1H), 3.65-3.88 (m, 3H), 3.42-3.50(m, 1H), 2.34-2.48 (m, 8H), 1.96 (d, J=4.02 Hz, 4H), 1.17 (t, J=7.40 Hz,3H).

Example 291.Cyclopropyl-{4-[4-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=390 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.88 (s, 1H),7.48-7.58 (m, 3H), 7.33 (dd, J=9.03, 1.76 Hz, 1H), 7.03 (d, J=8.78 Hz,2H), 4.58-4.67 (m, 1H), 3.77-4.02 (m, 2H), 3.62-3.73 (m, 2H), 2.44 (d,J=3.51 Hz, 6H), 1.75-2.11 (m, 5H), 0.97-1.05 (m, 2H), 0.74-0.81 (m, 2H).

Example 292.{4-[4-(7-Methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=406 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.95 (s, 1H),7.59 (d, J=1.26 Hz, 1H), 7.43-7.53 (m, 2H), 7.24 (s, 2H), 6.98 (d,J=8.78 Hz, 2H), 4.57-4.70 (m, 2H), 3.54-4.00 (m, 6H), 2.30-2.38 (m, 1H),2.26 (s, 3H), 1.87-2.12 (m, 7H).

Example 293.1-{4-[4-(7-Methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=364 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.94 (s, 1H),7.59 (d, J=1.25 Hz, 1H), 7.46-7.52 (m, 2H), 7.24 (s, 2H), 6.98 (d,J=8.53 Hz, 2H), 4.53-4.65 (m, 1H), 3.63-3.89 (m, 3H), 3.40-3.50 (m, 1H),2.38 (s, 2H), 2.26 (d, J=0.75 Hz, 3H), 1.79-2.04 (m, 4H), 1.18 (t,J=7.40 Hz, 3H).

Example 294.{4-[4-(5-Chloroimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=426 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.86 (d, J=0.75Hz, 1H), 7.74 (d, J=1.25 Hz, 1H), 7.64 (d, J=9.03 Hz, 1H), 7.41 (d,J=8.53 Hz, 2H), 7.24 (s, 1H), 7.01 (d, J=8.78 Hz, 2H), 4.59-4.70 (m,2H), 3.55-4.00 (m, 6H), 2.29-2.40 (m, 1H), 1.85-2.14 (m, 7H).

Example 295.{4-[4-(5-Chloroimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=426 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.86 (d, J=0.75Hz, 1H), 7.74 (d, J=1.25 Hz, 1H), 7.64 (d, J=9.03 Hz, 1H), 7.41 (d,J=8.53 Hz, 2H), 7.24 (s, 1H), 7.01 (d, J=8.78 Hz, 2H), 4.59-4.70 (m,2H), 3.55-4.00 (m, 6H), 2.29-2.40 (m, 1H), 1.85-2.14 (m, 7H).

Example 296.1-{4-[4-(5-Chloroimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=384 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.85-7.88 (m,1H), 7.74 (d, J=1.26 Hz, 1H), 7.64 (dd, J=9.03, 0.75 Hz, 1H), 7.41 (d,J=8.78 Hz, 2H), 7.24 (s, 1H), 6.98-7.04 (m, 2H), 4.57-4.65 (m, 1H), 3.71(d, J=3.51 Hz, 3H), 3.41-3.51 (m, 1H), 2.38 (s, 2H), 1.82-2.05 (m, 4H),1.18 (t, J=7.53 Hz, 3H).

Example 297.{4-[4-(5-Chloroimidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl})-cyclopropylmethanone

Analysis: LCMS m/z=396 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.86 (d, J=1.76Hz, 1H), 7.74 (d, J=1.51 Hz, 1H), 7.64 (dd, J=9.29, 0.75 Hz, 1H),7.39-7.44 (m, 2H), 7.24 (s, 1H), 6.99-7.06 (m, 2H), 4.61-4.67 (m, 1H),3.78-4.01 (m, 2H), 3.66-3.73 (m, 2H), 1.79 (s, 5H), 1.00 (dd, J=4.52,3.01 Hz, 2H), 0.78 (dd, J=8.03, 3.01 Hz, 2H).

Example 298.[4-(4-Imidazo[1,5-a]pyridin-6-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydro-furan-2-yl-methanone

Analysis: LCMS m/z=392 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.17 (s, 1H),8.05 (d, J=1.25 Hz, 1H), 7.42-7.53 (m, 4H), 6.93-7.05 (m, 3H), 4.58-4.70(m, 2H), 3.54-4.02 (m, 6H), 2.28-2.39 (m, 1H), 2.01 (s, 7H).

Example 299.1-[4-(4-Imidazo[1,5-a]pyridin-6-yl-phenoxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS m/z=350 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.14 (s, 1H),8.04 (q, J=1.17 Hz, 1H), 7.42-7.53 (m, 4H), 6.95-7.04 (m, 3H), 4.55-4.64(m, 1H), 3.64-3.87 (m, 3H), 3.39-3.48 (m, 1H), 2.39 (d, J=7.28 Hz, 2H),1.80-2.04 (m, 4H), 1.17 (t, J=7.40 Hz, 3H).

Example 300.Cyclopropyl-[4-(4-imidazo[1,5-a]pyridin-6-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS m/z=362 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.15 (s, 1H),8.05 (d, J=1.25 Hz, 1H), 7.42-7.53 (m, 4H), 7.02 (d, J=8.78 Hz, 3H),4.57-4.67 (m, 1H), 3.77-4.01 (m, 2H), 3.63-3.72 (m, 2H), 1.74-2.09 (m,5H), 0.97-1.04 (m, 2H), 0.75-0.82 (m, 2H).

Example 301.1-[4-(4-Imidazo[1,5-a]pyridin-6-yl-phenoxy)-piperidine-1-carbonyl]-cyclopropanecarboxylicacid amide

Analysis: LCMS m/z=405 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.15 (s, 1H),8.04 (d, J=1.25 Hz, 1H), 7.41-7.52 (m, 4H), 6.94-7.05 (m, 3H), 5.89-6.04(m, 1H), 5.33-5.47 (m, 1H), 4.60-4.67 (m, 1H), 3.67-3.90 (m, 4H),1.88-2.02 (m, 4H), 1.47-1.53 (m, 2H), 1.23-1.29 (m, 2H).

Example 302.(1-Hydroxycyclopropyl)-[4-(4-imidazo[1,5-a]pyridin-6-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS m/z=378 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.15 (s, 1H),8.05 (d, J=1.25 Hz, 1H), 7.42-7.54 (m, 4H), 6.94-7.06 (m, 3H), 4.59-4.66(m, 1H), 3.87-4.01 (m, 2H), 3.74 (br. s., 2H), 3.01-3.10 (m, 1H),1.96-2.07 (m, 2H), 1.83-1.94 (m, 2H), 1.12-1.18 (m, 2H), 0.96-1.03 (m,2H).

Example 303.(1-Hydroxycyclopropyl)-{4-[4-(8-methoxy-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=419 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.98 (dd,J=4.27, 1.76 Hz, 1H), 8.16 (dd, J=8.28, 1.76 Hz, 1H), 7.54-7.71 (m, 4H),7.41 (dd, J=8.16, 4.14 Hz, 1H), 7.02-7.08 (m, 2H), 4.58-4.72 (m, 1H),3.92-4.06 (m, 2H), 3.87 (s, 3H), 3.71-3.82 (m, 2H), 3.12-3.37 (m, 1H),2.01-2.08 (m, 2H), 1.88-1.98 (m, 2H), 1.15 (d, J=2.76 Hz, 2H), 0.99 (d,J=2.51 Hz, 2H).

Example 304.(1-Hydroxymethylcyclopropyl)-{4-[4-(5-methyl-imidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=406 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.74 (d, J=1.25Hz, 1H), 7.53-7.60 (m, 2H), 7.26-7.29 (m, 2H), 7.18 (d, J=9.03 Hz, 1H),7.00 (d, J=8.78 Hz, 2H), 4.59-4.66 (m, 1H), 3.84-3.95 (m, 2H), 3.68 (s,4H), 2.55 (s, 3H), 1.85-2.05 (m, 4H), 1.78-1.84 (m, 1H), 0.99-1.05 (m,2H), 0.80-0.85 (m, 2H).

Example 305.(1-Aminocyclopropyl)-{4-[4-(5-methyl-imidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=391 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.74 (d, J=1.25Hz, 1H), 7.53-7.61 (m, 2H), 7.28 (d, J=8.78 Hz, 2H), 7.18 (d, J=9.29 Hz,1H), 7.01 (d, J=8.78 Hz, 2H), 4.58-4.69 (m, 1H), 3.85-3.97 (m, 2H),3.68-3.78 (m, 2H), 2.55 (s, 3H), 1.76-2.08 (m, 6H), 1.04 (d, J=2.26 Hz,2H), 0.83 (d, J=2.26 Hz, 2H).

Example 306.(1-Hydroxycyclopropyl)-[4-(4-[1,2,4]triazolo[4,3-a]pyridin-7-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS m/z=379 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.81 (d, J=0.75Hz, 1H), 8.12-8.20 (m, 1H), 7.88-7.94 (m, 1H), 7.61 (d, J=8.78 Hz, 2H),7.13-7.17 (m, 1H), 7.05 (d, J=8.78 Hz, 2H), 4.59-4.71 (m, 1H), 3.87-4.02(m, 2H), 3.68-3.82 (m, 2H), 2.90-2.98 (m, 1H), 1.97-2.09 (m, 2H),1.84-1.94 (m, 2H), 1.12-1.19 (m, 2H), 0.97-1.04 (m, 2H).

Example 307.(R)-Tetrahydrofuran-2-yl-[4-(4-[1,2,4]triazolo[4,3-a]pyridin-7-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS m/z=393 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.80 (d, J=0.75Hz, 1H), 8.15 (dd, J=7.28, 1.00 Hz, 1H), 7.88-7.93 (m, 1H), 7.61 (d,J=8.53 Hz, 2H), 7.13 (dd, J=7.28, 1.76 Hz, 1H), 7.04 (d, J=8.78 Hz, 2H),4.59-4.71 (m, 2H), 3.51-4.01 (m, 6H), 2.28-2.39 (m, 1H), 1.87-2.11 (m,7H).

Example 308.Cyclopropyl-[4-(4-[1,2,4]triazolo[4,3-a]pyridin-7-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS m/z=363 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.81 (s, 1H),8.15 (dd, J=7.03, 1.00 Hz, 1H), 7.86-7.95 (m, 1H), 7.61 (d, J=8.78 Hz,2H), 7.14 (dd, J=7.15, 1.63 Hz, 1H), 7.03-7.10 (m, 2H), 4.60-4.70 (m,1H), 3.77-4.02 (m, 2H), 3.68 (ddd, J=13.36, 6.96, 4.02 Hz, 2H), 2.01 (s,4H), 1.79 (t, J=4.64 Hz, 1H), 1.00 (dd, J=4.52, 3.01 Hz, 2H), 0.78 (dd,J=7.78, 3.01 Hz, 2H).

Example 309.(1-Hydroxycyclopropyl)-{4-[4-(5-methyl-imidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=392 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.81 (s, 1H),8.15 (dd, J=7.03, 1.00 Hz, 1H), 7.86-7.95 (m, 1H), 7.61 (d, J=8.78 Hz,2H), 7.14 (dd, J=7.15, 1.63 Hz, 1H), 7.03-7.10 (m, 2H), 4.60-4.70 (m,1H), 3.77-4.02 (m, 2H), 3.68 (ddd, J=13.36, 6.96, 4.02 Hz, 2H), 2.01 (s,4H), 1.79 (t, J=4.64 Hz, 1H), 1.00 (dd, J=4.52, 3.01 Hz, 2H), 0.78 (dd,J=7.78, 3.01 Hz, 2H).

Example 310.2-Hydroxy-2-methyl-1-{4-[4-(5-methyl-imidazo[1,2-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=394 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.74 (d, J=1.25Hz, 1H), 7.56-7.61 (m, 1H), 7.54 (s, 1H), 7.29 (s, 2H), 7.17-7.22 (m,1H), 7.00 (d, J=8.78 Hz, 2H), 4.62-4.71 (m, 1H), 4.49 (s, 1H), 3.81-3.94(m, 2H), 3.73 (s, 2H), 2.55 (s, 3H), 1.88-2.06 (m, 4H), 1.53 (s, 6H).

Example 311.{4-[4-(5-Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=407 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.39 (s, 1H),7.67 (s, 1H), 7.49 (d, J=9.03 Hz, 1H), 7.30 (d, J=8.53 Hz, 2H), 7.02 (d,J=8.78 Hz, 2H), 4.57-4.72 (m, 2H), 3.53-4.04 (m, 6H), 2.78 (s, 3H),2.28-2.40 (m, 1H), 1.88-2.13 (m, 7H).

Example 312.(1-Hydroxycyclopropyl)-{4-[4-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=393 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.39 (s, 1H),7.66-7.73 (m, 1H), 7.47-7.54 (m, 1H), 7.28-7.34 (m, 2H), 7.30 (d, J=8.78Hz, 2H), 7.03 (d, J=8.78 Hz, 2H), 4.61-4.69 (m, 1H), 3.90-4.03 (m, 2H),3.69-3.81 (m, 2H), 2.78 (s, 4H), 1.99-2.09 (m, 2H), 1.87-1.97 (m, 2H),1.14-1.19 (m, 2H), 1.00 (d, J=2.76 Hz, 2H).

Example 313.1-{4-[4-(5-Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl})-propan-1-one

Analysis: LCMS m/z=365 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.39 (s, 1H),7.69 (d, J=9.04 Hz, 1H), 7.49 (d, J=9.03 Hz, 1H), 7.30 (d, J=8.78 Hz,2H), 7.02 (d, J=8.78 Hz, 2H), 4.56-4.67 (m, 1H), 3.63-3.91 (m, 3H),3.38-3.51 (m, 1H), 2.78 (s, 3H), 2.34-2.47 (m, 2H), 1.83-2.06 (m, 4H),1.18 (s, 3H).

Example 314.Cyclopropyl-{4-[4-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=377 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.39 (s, 1H),7.63-7.73 (m, 1H), 7.50 (d, J=9.29 Hz, 1H), 7.30 (d, J=8.78 Hz, 2H),7.03 (d, J=8.78 Hz, 2H), 4.58-4.69 (m, 1H), 3.77-4.02 (m, 2H), 3.63-3.74(m, 2H), 2.78 (s, 3H), 1.72-2.12 (m, 6H), 0.95-1.05 (m, 2H), 0.75-0.81(m, 2H).

Example 315.{4-[4-(8-Methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(1-trifluoro-methylcyclopropyl)-methanone

Analysis: LCMS m/z=455 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.99 (dd,J=4.27, 1.76 Hz, 1H), 8.16 (dd, J=8.28, 1.76 Hz, 1H), 7.70 (d, J=8.53Hz, 1H), 7.46 (d, J=8.28 Hz, 1H), 7.42 (dd, J=8.28, 4.27 Hz, 1H),7.32-7.38 (m, 2H), 6.98-7.05 (m, 2H), 4.66 (t, J=3.51 Hz, 1H), 3.81 (br.s., 4H), 2.77 (s, 3H), 1.91-2.08 (m, 4H), 1.31-1.42 (m, 2H), 1.19 (s,2H).

Example 316.(1-Aminocyclopropyl)-{4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=402 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.94-9.08 (m,1H), 8.13-8.21 (m, 1H), 7.66-7.74 (m, 1H), 7.45-7.50 (m, 1H), 7.38-7.45(m, 1H), 7.32-7.38 (m, 2H), 7.00-7.07 (m, 2H), 4.60-4.72 (m, 1H),3.86-3.98 (m, 2H), 3.73 (dd, J=6.90, 4.14 Hz, 2H), 2.77 (s, 3H),1.98-2.08 (m, 2H), 1.78-1.98 (m, 4H), 1.01-1.08 (m, 2H), 0.79-0.88 (m,2H).

Example 317.{4-[4-(1-Methyl-1H-indazol-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone;compound with trifluoroacetic acid

Analysis: LCMS m/z=406 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.04 (1H, d,J=1.0 Hz), 7.78 (1H, dd, J=8.5, 0.8 Hz), 7.61 (2H, d, J=8.5 Hz), 7.50(1H, s), 7.40 (1H, dd, J=8.4, 1.4 Hz), 6.96-7.07 (2H, m), 4.66-4.72 (1H,m), 4.09-4.19 (3H, m), 3.40-4.05 (6H, m), 1.80-2.34 (8H, m).

Example 318.[4-(4-Imidazo[1,2-a]pyridin-6-yl-phenoxy)-piperidin-1-yl]-(R)-tetrahydro-furan-2-yl-methanone;compound with trifluoroacetic acid

Analysis: LCMS m/z=392 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.26 (1H, s),7.58-7.72 (3H, m), 7.48 (2H, d, J=8.5 Hz), 7.39 (1H, dd, J=9.3, 1.8 Hz),7.02 (2H, d, J=8.5 Hz), 4.57-4.72 (2H, m), 3.43-4.03 (6H, m), 2.31 (1H,br. s.), 1.80-2.14 (7H, m).

Example 319.1-{4-[4-(8-Methylquinolin-7-yl)-phenoxy]-piperidine-1-carbonyl}-cyclopropanecarbonitrile

Analysis: LCMS m/z=412 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.99 (dd,J=4.27, 1.76 Hz, 1H), 8.16 (dd, J=8.28, 1.76 Hz, 1H), 7.70 (d, J=8.28Hz, 1H), 7.47 (d, J=8.53 Hz, 1H), 7.33-7.44 (m, 3H), 6.99-7.09 (m, 2H),4.68-4.77 (m, 1H), 3.65-4.10 (m, 4H), 2.77 (s, 3H), 1.94-2.19 (m, 4H),1.65 (br. s., 4H).

Example 320.(1-Methylcyclopropyl)-{4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=401 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.99 (dd,J=4.14, 1.88 Hz, 1H), 8.11-8.20 (m, 1H), 7.69 (s, 1H), 7.47 (d, J=8.53Hz, 1H), 7.39-7.45 (m, 1H), 7.35 (d, J=8.53 Hz, 2H), 7.02 (d, J=8.78 Hz,2H), 4.57-4.68 (m, 1H), 3.85-4.00 (m, 2H), 3.61-3.76 (m, 2H), 2.77 (s,3H), 1.84-2.05 (m, 4H), 1.34 (s, 3H), 0.96 (d, J=1.76 Hz, 2H), 0.60 (d,J=1.76 Hz, 2H).

Example 321.((S)-2,2-Dimethylcyclopropyl)-{4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=415 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.99 (dd,J=4.02, 1.76 Hz, 1H), 8.16 (dd, J=8.16, 1.63 Hz, 1H), 7.70 (d, J=8.53Hz, 1H), 7.48 (s, 1H), 7.42 (dd, J=8.03, 4.27 Hz, 1H), 7.35 (d, J=8.53Hz, 2H), 7.03 (d, J=8.53 Hz, 2H), 4.63 (br. s., 1H), 3.56-4.02 (m, 4H),2.77 (s, 3H), 1.82-2.14 (m, 4H), 1.18-1.28 (m, 5H), 1.08 (br. s., 3H),0.68-0.77 (m, 1H).

Example 322.(2,2-Dimethylcyclopropyl)-{4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=415 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.99 (dd,J=3.89, 1.38 Hz, 1H), 8.16 (dd, J=8.16, 1.38 Hz, 1H), 7.70 (d, J=8.53Hz, 1H), 7.39-7.51 (m, 2H), 7.35 (d, J=8.28 Hz, 2H), 7.03 (d, J=8.53 Hz,2H), 4.63 (br. s., 1H), 3.59-4.02 (m, 4H), 2.77 (s, 3H), 1.84-2.12 (m,4H), 1.14-1.26 (m, 5H), 1.07 (d, J=1.76 Hz, 3H), 0.73 (dd, J=7.78, 4.52Hz, 1H).

Example 323.[4-[4-[8-(4-Methylpiperazin-1-yl)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone

Method A Step 1 tert-Butyl4-[4-[8-(4-methylpiperazin-1-yl)-7-quinolyl]phenoxy]piperidine-1-carboxylate

To an oven dried flask under an atmosphere of argon was added tert-butyl4-[4-(8-chloro-7-quinolyl)phenoxy]piperidine-1-carboxylate (0.200 g,0.456 mmol), 1-methylpiperazine (0.06 mL, 0.5 mmol), palladium acetate(6.1 mg, 0.027 mmol), biphenyl-2-yl-di-tert-butyl-phosphane (16.3 mg,0.0547 mmol), sodium tert-butoxide (0.0701 g, 0.729 mmol), followed bytoluene (5 mL). The reaction mixture was purged under a nitrogenatmosphere and was stirred at 99° C. overnight. The reaction stillcontained ˜50% unreacted starting material. Additional sodiumtert-butoxide (0.0701 g, 0.729 mmol),biphenyl-2-yl-di-tert-butyl-phosphane (16.3 mg, 0.0547 mmol), palladiumacetate (6.1 mg, 0.027 mmol), 1-methylpiperazine (0.06 mL, 0.5 mmol)were added. The reaction mixture was stirred for an additional 4 h. Thesolvent was evaporated under reduced pressure. The solids were dilutedwith brine (50 mL), extracted with EtOAc (3×50 mL), dried (Na₂SO₄) andthe solvent evaporated under reduced pressure. The crude product waspurified by on HPLC (reverse phase, 5-55% ACN/H₂O). The combined aqueousfractions were diluted with saturated Na₂CO₃ (25 mL) extracted with DCM(3×30 mL) to give tert-butyl4-[4-[8-(4-methylpiperazin-1-yl)-7-quinolyl]phenoxy]piperidine-1-carboxylate(free base) as an off-white foam (50 mg, 20%); Analysis: LCMS m/z=503(M+1); ¹H NMR (400 MHz, CDCl₃) δ: 7.85-7.92 (m, 2H), 7.60-7.70 (m, 3H),7.43-7.49 (m, 1H), 6.93-7.05 (m, 3H), 4.47-4.59 (m, 1H), 3.66-3.84 (m,6H), 3.31-3.43 (m, 2H), 2.52-2.60 (m, 4H), 2.37 (s, 3H), 1.92-2.00 (m,2H), 1.74-1.86 (m, 2H), 1.48 (s, 9H).

Step 2. 8-(4-Methylpiperazin-1-yl)-7-[4-(4-piperidyloxy)phenyl]quinolinehydrochloride

To a stirred solution of tert-butyl4-[4-[8-(4-methylpiperazin-1-yl)-7-quinolyl]-phenoxy]piperidine-1-carboxylate(50 mg, 0.1 mmol) in DCM (1 mL) was added 4.0 M of HCl in 1,4-dioxane(0.25 mL, 0.99 mmol) dropwise. The reaction was stirred at 35° C. 4 hand was concentrated under reduced pressure. The crude contents werere-dissolved in DCM (2×30 mL) and concentrated under reduced pressure.The crude product was trituated with Et₂O (2×50 mL) to give the8-(4-methylpiperazin-1-yl)-7-[4-(4-piperidyloxy)phenyl]quinoline HCl asan yellow solid (43 mg, 90%); Analysis: LCMS m/z=403 (M+1). Thismaterial was used in the next step without further purification.

Step 3.[4-[4-[8-(4-methylpiperazin-1-yl)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone

A solution of (R)-tetrahydrofuran-2-carboxylic acid (0.01 mL, 0.1 mmol),HATU (40 mg, 0.1 mmol) and DIPEA (0.07 mL, 0.4 mmol) in acetonitrile(0.4 mL) was stirred at room temperature for 10 min.8-(4-Methylpiperazin-1-yl)-7-[4-(4-piperidyloxy)phenyl]quinolinedihydrochloride (43 mg, 0.098 mmol) was added and the mixture wasstirred at room temperature for 1 h. The reaction was quenched by theaddition of MeOH (1 mL) and the solvent was evaporated in vacuo. Thecrude product was purified by on HPLC (reverse phase, 5-50% ACN/H₂O).The combined aqueous fractions were diluted with saturated Na₂CO₃ (25mL) extracted with DCM (3×30 mL) to give the desired product (free base)as on off-white foam. The compound was lyophilized to give[4-[4-[8-(4-methylpiperazin-1-yl)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanoneas an off-white solid (20 mg, 39%); Analysis: LCMS m/z=501 (M+1); ¹H NMR(400 MHz, CDCl₃) δ: 7.83-7.95 (m, 2H), 7.65 (dd, J=14.31, 8.28 Hz, 3H),7.46 (dd, J=8.16, 1.38 Hz, 1H), 6.93-7.05 (m, 3H), 4.56-4.69 (m, 2H),3.53-4.01 (m, 10H), 2.57 (t, J=4.64 Hz, 4H), 2.37 (s, 3H), 2.27-2.34 (m,1H), 1.84-2.12 (m, 7H).

Example 324.[4-[4-(8-Amino-7-quinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone

Method B Step 1. tert-Butyl4-[4-(8-amino-7-quinolyl)phenoxy]piperidine-1-carboxylate

tert-Butyl 4-[4-(8-chloro-7-quinolyl)phenoxy]piperidine-1-carboxylate(0.300 g, 0.683 mmol), palladium acetate (15 mg, 0.068 mmol), (±)-BINAP(85 mg, 0.14 mmol), dicesium carbonate (668 mg, 2.05 mmol) andbenzophenone imine (0.14 mL, 0.82 mmol) in toluene (6 mL) was degassedunder an atmosphere of argon, then heated at 100° C. for 4 h. Thesolvent was then evaporated under reduced pressure. The solids werediluted with brine (50 mL), extracted with EtOAc (3×50 mL), dried(Na₂SO₄) and concentrated under reduced pressure. The resulting oil waspurified on HPLC (reverse phase, 20-70% ACN/H₂O). The combined aqueousfractions were diluted with sat. Na₂CO₃ (50 mL) extracted with DCM (3×60mL) to give the desired product (free base) as a brown oil. The crudeproduct was purified by silica gel chromatography (0-50% EtOAc/hexanes)to give tert-butyl4-[4-(8-amino-7-quinolyl)phenoxy]piperidine-1-carboxylate as anoff-yellow oil (50 mg; 20%); Analysis: LCMS m/z=420 (M+1); ¹H NMR (400MHz, CDCl₃) δ: 8.78 (dd, J=4.14, 1.63 Hz, 1H), 8.08 (dd, J=8.28, 1.51Hz, 1H), 7.46-7.56 (m, 2H), 7.31-7.42 (m, 2H), 7.19 (d, J=8.28 Hz, 1H),7.00-7.09 (m, 2H), 5.04-5.29 (m, 2H), 4.53 (s, 1H), 3.67-3.83 (m, 2H),3.37 (ddd, J=13.43, 7.78, 3.89 Hz, 2H), 1.96 (br. s., 2H), 1.82 (d,J=3.76 Hz, 2H), 1.49 (s, 9H).

Step 2. 7-[4-(4-Piperidyloxy)phenyl]quinolin-8-amine HCl

To a stirred solution of tert-butyl4-[4-(8-amino-7-quinolyl)phenoxy]piperidine-1-carboxylate (50 mg, 0.1mmol) in DCM (2 mL) was added 4.0 M of HCl in 1,4-dioxane (0.30 mL, 1.2mmol) solution dropwise. The reaction was stirred at 35° C. 4 h and wasthen concentrated under reduced pressure. The crude contents werere-dissolved in DCM (2×30 mL) and concentrated under reduced pressure togive the desired product as yellow foam. The crude product was trituatedwith Et₂O (2×10 mL) to give 7-[4-(4-piperidyloxy)phenyl]quinolin-8-amineHCl as an yellow solid (35 mg; 80%); Analysis: LCMS m/z=320 (M+1). Thismaterial was used without further purification.

Step 3.[4-[4-(8-Amino-7-quinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone

A solution of (R)-tetrahydrofuran-2-carboxylic acid (0.01 mL, 0.a mmol),HATU (39 mg, 0.10 mmol) and DIPEA (0.069 mL, 0.39 mmol) in acetonitrile(0.4 mL) was stirred at room temperature for 10 min.7-[4-(4-piperidyloxy)phenyl]quinolin-8-amine HCl (35 mg, 0.098 mmol) wasadded and the mixture was stirred at room temperature for 1 hour. Thereaction was quenched by addition of MeOH (1 mL). The solvent wasevaporated in vacuo. The crude product was purified by HPLC (reversephase, 13-55% ACN/H₂O). The combined aqueous fractions were diluted withsat. Na₂CO₃ (25 mL) extracted with DCM (3×30 mL) to give the desiredproduct (free base) as an yellow foam. The product was trituated withEt₂O (5 mL) and hexanes (5 mL) to give[4-[4-(8-amino-7-quinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanoneas a light yellow solid (8 mg; 20%); Analysis: LCMS m/z=418 (M+1); ¹HNMR (400 MHz, CDCl₃) δ: 8.80 (br. s., 1H), 8.16 (d, J=7.28 Hz, 1H), 7.51(d, J=8.28 Hz, 2H), 7.34-7.46 (m, 2H), 7.22 (d, J=8.28 Hz, 1H), 7.05 (d,J=8.53 Hz, 2H), 4.68-6.04 (m, 2H), 4.65 (d, J=6.02 Hz, 2H), 3.55-4.02(m, 6H), 2.26-2.40 (m, 1H), 1.87-2.14 (m, 7H).

The following compounds were synthesized using the procedures ofExamples 323 or 324.

Example 325.{4-[4-(8-Methylaminoquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=432 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.77 (dd,J=4.14, 1.63 Hz, 1H), 8.09 (dd, J=8.16, 1.63 Hz, 1H), 7.51 (d, J=8.53Hz, 2H), 7.33-7.42 (m, 2 H), 7.21 (d, J=8.53 Hz, 1H), 6.94-7.02 (m, 2H),6.31-6.42 (m, 1H), 4.66 (dd, J=7.15, 5.65 Hz, 2H), 3.56-4.01 (m, 6H),2.58 (s, 3H), 2.25-2.38 (m, 1H), 1.93 (br. s., 7H).

Example 326.1-{4-[4-(8-Methylaminoquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=390 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.77 (dd,J=4.27, 1.76 Hz, 1H), 8.09 (dd, J=8.28, 1.76 Hz, 1H), 7.47-7.56 (m, 2H),7.33-7.44 (m, 2H), 7.21 (d, J=8.28 Hz, 1H), 6.98 (d, J=8.78 Hz, 2H),6.31-6.45 (m, 1H), 4.60 (dt, J=6.53, 3.26 Hz, 1H), 3.80-3.90 (m, 1H),3.63-3.79 (m, 2H), 3.39-3.51 (m, 1H), 2.58 (s, 3H), 2.36-2.45 (m, 2H),1.80-2.05 (m, 4H), 1.18 (t, J=7.53 Hz, 3H).

Example 327.(4-{4-[8-(2-Methoxyethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=476 (M+1); ¹H NMR (400 MHz, CD₃OD): δ: 8.82 (dd,J=4.27, 1.76 Hz, 1H), 8.23 (dd, J=8.28, 1.76 Hz, 1H), 7.55 (d, J=8.53Hz, 2H), 7.46-7.51 (m, 1H), 7.38 (s, 2H), 7.10 (d, J=8.53 Hz, 2H),4.70-4.83 (m, 2H), 3.90 (s, 4H), 3.61-3.74 (m, 1H), 3.49-3.60 (m, 1H),3.35-3.39 (m, 4H), 3.26 (s, 3H), 2.98 (t, J=5.40 Hz, 2H), 2.19-2.32 (m,1H), 1.78-2.15 (m, 7H).

Example 328.1-(4-{4-[8-(2-Methoxyethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one

Analysis: LCMS m/z=434 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.80 (dd,J=4.02, 1.51 Hz, 1H), 8.08 (dd, J=8.28, 1.51 Hz, 1H), 7.53 (d, J=8.53Hz, 2H), 7.30-7.42 (m, 2H), 7.20-7.25 (m, 1H), 6.98 (d, J=8.53 Hz, 2H),6.57 (br. s., 1H), 4.60 (br. s., 1H), 3.80-3.94 (m, 1H), 3.61-3.80 (m,2H), 3.41-3.53 (m, 1H), 3.37 (t, J=5.52 Hz, 2H), 3.27 (s, 3H), 2.99 (t,J=5.40 Hz, 2H), 2.39 (q, J=7.45 Hz, 2H), 1.81-2.05 (m, 4H), 1.18 (t,J=7.53 Hz, 3H).

Example 329.(4-{4-[8-(2-Dimethylaminoethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=489 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.79 (dd,J=4.02, 1.76 Hz, 1H), 8.08 (dd, J=8.28, 1.76 Hz, 1H), 7.52 (d, J=8.28Hz, 2H), 7.31-7.44 (m, 2H), 7.23 (d, J=8.53 Hz, 1H), 6.96-7.03 (m, 2H),6.25-6.73 (m, 1H), 4.66 (dd, J=7.40, 5.65 Hz, 2H), 3.52-4.02 (m, 6H),2.90 (t, J=6.53 Hz, 2H), 2.38 (t, J=6.40 Hz, 2H), 2.28-2.34 (m, 1H),2.15 (s, 6H), 1.86-2.10 (m, 7H).

Example 330.7-[4-(1-Propionyl-piperidin-4-yloxy)-phenyl]-quinoline-8-carbonitrile

An oven dried round bottom flask was added1-[4-[4-(8-chloro-7-quinolyl)-phenoxy]-1-piperidyl]propan-1-one (120 mg,0.30 mmol), zinc cyanide (54 mg, 0.46 mmol), activated powdered zinc (4mg, 0.06 mmol),[1,1′bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex(DPPF-Pd) with DCM (1:1) (12 mg, 0.015 mmol) and DMF (1 mL) under anatmosphere of nitrogen. The reaction mixture was heated at 90° C. andstirred overnight under an atmosphere of nitrogen. The reaction mixturewas cooled rt and filtered through Celite, washed with EtOAc (2×20 mL)and concentrated under reduced pressure. The crude product was purifiedby HPLC (reverse phase, 23-65% ACN/H₂O). The combined aqueous fractionswere diluted with sat. Na₂CO₃ (25 mL), extracted with DCM (3×30 mL) togive the desired product (free base) as an yellow oil. The sample waslyophilized overnight to give7-[4-(1-propionyl-piperidin-4-yloxy)-phenyl]-quinoline-8-carbonitrile ason off-white solid (4.1 mg; 3.3%); Analysis: LCMS m/z=386 (M+1); ¹H NMR(400 MHz, CDCl₃) δ: 9.14 (dd, J=4.27, 1.76 Hz, 1H), 8.22-8.29 (m, 1H),8.06 (d, J=8.53 Hz, 1H), 7.70 (dd, J=8.78, 1.00 Hz, 3H), 7.52-7.57 (m,1H), 7.06-7.12 (m, 2H), 4.61-4.70 (m, 1H), 3.78-3.90 (m, 1H), 3.65-3.77(m, 2H), 3.40-3.51 (m, 1H), 2.40 (d, J=7.78 Hz, 2H), 1.95-2.05 (m, 2H),1.81-1.92 (m, 2H), 1.17-1.21 (m, 3H).

Example 331.[4-[4-[8-(Dimethylamino)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone

Step 1. Trifluoromethanesulfonic acid 7-bromoquinolin-8-yl ester

To a solution of 7-bromoquinolin-8-ol (5 g, 20 mmol) in DCM (120 mL) at0° C. was added pyridine (9.02 mL, 112 mmol) andtrifluoromethanesulfonic (triflic) anhydride (5.63 mL, 33.5 mmol). Afterstirring for 30 min at 0° C., the reaction was quenched with aq. sat.NaHCO₃ solution (25 mL). The organic layer was separated and the waterlayer was extracted with DCM (2×30 mL). The combined organic layers waswashed with water (50 mL), brine (50 mL), dried (Na₂SO₄), andconcentrated to give trifluoromethanesulfonic acid 7-bromoquinolin-8-ylester as a grayish solid (7 g; 79%); LCMS m/z=357 (M+1). This materialwas used for next the step without further purification.

Step 2.4-[4-(8-Trifluoromethanesulfonyloxy-quinolin-7-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester

A flask charged with4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (5 g, 10 mmol), trifluoromethanesulfonic acid7-bromo-quinolin-8-yl ester (4.86 g, 13.6 mmol), palladium acetate (280mg, 1.2 mmol), triphenylphosphine (0.65 g, 2.5 mmol), 1,4-dioxane (60mL) and 1.0 M of Na₂CO₃ in H₂O (62.0 mL, 62.0 mmol) was flashed withnitrogen for 5 min. The reaction was heated at 85° C. for 1.5 h. Aftercooling to room temp, the reaction was diluted with EtOAc (200 mL),washed with an aq. sat. NaHCO₃ solution (100 mL). The water layer wasback-extracted with EtOAc (2×50 mL). The combined organic layers waswashed with brine (50 mL), dried (Na₂SO₄), and concentrated. The crudewas purified by silica gel chromatography (0-50% EtOAc/hexanes) to give4-[4-(8-trifluoromethanesulfonyloxy-quinolin-7-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester as a white solid (5 g; 60%); Analysis: LCMSm/z=553 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.06-9.10 (m, 1H), 8.20-8.28(m, 1H), 7.87 (d, J=8.53 Hz, 1H), 7.62 (d, J=8.53 Hz, 1H), 7.50-7.56 (m,3H), 7.05 (d, J=9.03 Hz, 2H), 4.48-4.63 (m, 1H), 3.69-3.80 (m, 2H),3.29-3.44 (m, 2H), 1.92-2.03 (m, 2H), 1.75-1.85 (m, 2H), 1.48 (s, 9H).

Step 3. tert-Butyl4-[4-[8-(dimethylamino)-7-quinolyl]phenoxy]piperidine-1-carboxylate

To an oven dried flask under an atmosphere of argon was added4-[4-(8-trifluoro-methanesulfonyloxy-quinolin-7-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (1 g, 2 mmol), dimethylamine (2M solution in THF,10.3 mL, 22.8 mmol), palladium acetate (51 mg, 0.23 mmol), (±)-BINAP(142 mg, 0.228 mmol), cesium carbonate (1.039 g, 3.189 mmol), followedby THF (10 mL). The reaction mixture was purged under an atmosphere ofargon and was stirred at 65° C. for 20 h in a sealed tube. The solventwas evaporated under reduced pressure. The solids were diluted withbrine (250 mL), extracted with EtOAc (3×50 mL), dried (Na₂SO₄) and thesolvent evaporated under reduced pressure. The crude product waspurified by on silica gel chromatography (0-30% EtOAc/hexanes). Thecombined aqueous fractions were evaporated under reduced pressure toyield the desired product as an yellow solid (420 mg; 40%). Analysis:LCMS m/z=448 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.94 (dd, J=4.14, 1.88Hz, 1H), 8.11 (dd, J=8.28, 1.76 Hz, 1H), 7.46-7.52 (m, 1H), 7.32-7.42(m, 4H), 6.99 (d, J=8.78 Hz, 2H), 4.50-4.58 (m, 1H), 3.70-3.81 (m, 2H),3.32-3.42 (m, 2H), 2.89 (s, 6H), 1.94-2.01 (m, 2H), 1.81 (dd, J=13.18,3.89 Hz, 2H), 1.48 (s, 9H).

Step 4. N,N-Dimethyl-7-[4-(4-piperidyloxy)phenyl]quinolin-8-aminehydrochloride

To a stirred solution of tert-butyl4-[4-[8-(dimethylamino)-7-quinolyl]phenoxy]-piperidine-1-carboxylate(420 mg, 0.94 mmol) in DCM (10 mL) was added 4.0 M of HCl in 1,4-dioxane(2.35 mL, 9.38 mmol) dropwise. The reaction was stirred at 35° C. (4 h)and was concentrated under reduced pressure. The crude contents werere-dissolved in DCM (2×30 mL) and concentrated under reduced pressure.The crude product was trituated with Et₂O (2×25 mL) to give the desiredN,N-dimethyl-7-[4-(4-piperidyloxy)phenyl]quinolin-8-amine HCl as anyellow solid (360 mg; 95%); LCMS m/z=348 (M+1). Used without furtherpurification.

Step 5.[4-[4-[8-(Dimethylamino)-7-quinolyl]phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone

A solution of (R)-tetrahydrofuran-2-carboxylic acid (0.04 mL, 0.4 mmol),HATU (156 mg, 0.410 mmol) and DIPEA (0.27 mL, 1.6 mmol) in acetonitrile(2 mL) was stirred at room temperature for 10 min. [A]N,N-dimethyl-7-[4-(4-piperidyloxy)phenyl]quinolin-8-amine HCl (150 mg,0.39 mmol) was added and the mixture was stirred at room temperature for1 hour. The reaction was quenched by the addition of MeOH (1 mL). Thesolvent was evaporated in vacuo. The crude product was purified by onHPLC (reverse phase, 10-55% ACN/H₂O). The combined aqueous fractionswere diluted with sat. Na₂CO₃ (25 mL) extracted with DCM (3×30 mL) togive the desired product (free base) as a an yellow solid (120 mg; 66%).Analysis: LCMS m/z=446 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.95 (dd,J=4.14, 1.88 Hz, 1H), 8.09-8.16 (m, 1H), 7.46-7.56 (m, 1H), 7.32-7.42(m, 4H), 6.93-7.06 (m, 2H), 4.55-4.73 (m, 2H), 3.53-4.04 (m, 6H), 2.90(s, 6H), 2.26-2.41 (m, 1H), 1.89-2.14 (m, 7H).

The following compounds were synthesized using the procedure for example331:

Example 332.1-{4-[4-(8-Dimethylaminoquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=404 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.95 (dd,J=4.02, 1.76 Hz, 1H), 8.09-8.16 (m, 1H), 7.47-7.54 (m, 1H), 7.32-7.43(m, 4H), 7.00 (d, J=8.53 Hz, 2H), 4.53-4.66 (m, 1H), 3.61-3.92 (m, 3H),3.40-3.50 (m, 1H), 2.90 (s, 6H), 2.36-2.46 (m, 2H), 1.94-2.05 (m, 2H),1.84-1.92 (m, 2H), 1.18 (t, J=7.53 Hz, 3H).

Example 333.Cyclopropyl-{4-[4-(8-dimethylamino-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=416 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.95 (dd,J=4.27, 1.76 Hz, 1H), 8.08-8.18 (m, 1H), 7.47-7.56 (m, 1H), 7.33-7.44(m, 4H), 7.01 (d, J=8.78 Hz, 2H), 4.57-4.68 (m, 1H), 3.82-4.02 (m, 2H),3.64-3.73 (m, 2H), 2.90 (s, 6H), 2.01 (s, 5H), 1.01 (br. s., 2H), 0.78(dd, J=8.03, 3.01 Hz, 2H).

Example 334.(4-{4-[8-(2-Pyrrolidin-1-yl-ethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-(R)-tetrahydrofuran-2-yl-methanone

Analysis: LCMS m/z=515 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.78 (dd,J=4.02, 1.76 Hz, 1H), 8.05-8.12 (m, 1H), 7.53 (d, J=8.53 Hz, 2H), 7.34(d, J=8.53 Hz, 2H), 7.23 (s, 1H), 6.98 (d, J=8.78 Hz, 2H), 6.36-6.76 (m,1H), 4.58-4.70 (m, 2H), 3.48-4.04 (m, 6H), 2.94 (s, 2H), 2.54 (s, 2H),2.24-2.40 (m, 5H), 1.84-2.13 (m, 7H), 1.70 (s, 4H).

Example 335.1-(4-{4-[8-(2-Pyrrolidin-1-yl-ethylamino)-quinolin-7-yl]-phenoxy}-piperidin-1-yl)-propan-1-one

Analysis: LCMS m/z=473 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 8.78 (dd,J=4.27, 1.76 Hz, 1H), 8.08 (dd, J=8.28, 1.76 Hz, 1H), 7.50-7.57 (m, 2H),7.30-7.40 (m, 2H), 7.22 (d, J=8.53 Hz, 1H), 6.92-7.02 (m, 2H), 6.32-6.75(m, 1H), 4.52-4.67 (m, 1H), 3.63-3.90 (m, 3H), 3.39-3.51 (m, 1H), 2.94(s, 2H), 2.54 (t, J=6.78 Hz, 2H), 2.33-2.45 (m, 6H), 1.82-2.02 (m, 4H),1.68-1.76 (m, 4H), 1.18 (t, J=7.40 Hz, 3H)

Example 336. 7-[4-[[1-[(2R)-Tetrahydrofuran-2-carbonyl]-4piperidyl]oxy]phenyl]quinoline-8-carboxamide

Step 1. tert-Butyl4-[4-(8-cyano-7-quinolyl)phenoxy]piperidine-1-carboxylate

An oven dried round bottom flask was loaded with4-[4-(8-trifluoromethane-sulfonyloxy-quinolin-7-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (1 g, 2 mmol), zinc cyanide (319 mg, 2.71 mmol),activated, powdered zinc (24 mg, 0.36 mmol), DPPF-Pd(II), complex withDCM (1:1) (74 mg, 0.090 mmol), and DMF (6 mL) under an atmosphere ofnitrogen. The reaction mixture was lowered in a mantle pre-heated at 90°C. and stirred overnight at this temperature under an atmosphere ofnitrogen. The reaction mixture was cooled to RT and filtered throughCelite, washed with EtOAc (2×20 mL) and concentrated under reducedpressure. The crude product was purified by silica gel chromatography(0-60% EtOAc/hexanes). The combined fractions were evaporated underreduced pressure to give the tert-butyl4-[4-(8-cyano-7-quinolyl)phenoxy]piperidine-1-carboxylate as a whitesolid (750 mg, 90%). Analysis: LCMS m/z=430 (M+1); ¹H NMR (400 MHz,CDCl₃) δ: 9.10-9.22 (m, 1H), 8.21-8.30 (m, 1H), 8.05 (s, 1H), 7.69 (dd,J=8.66, 1.13 Hz, 3H), 7.50-7.59 (m, 1H), 7.07 (d, J=8.78 Hz, 2H),4.52-4.67 (m, 1H), 3.65-3.83 (m, 2H), 3.32-3.49 (m, 2H), 1.94-2.03 (m,2H), 1.78-1.88 (m, 2H), 1.48 (s, 9H).

Step 2. 7-[4-(4-Piperidyloxy)phenyl]quinoline-8-carboxamide;2,2,2-trifluoroacetic acid

To a stirred solution of tert-butyl4-[4-(8-cyano-7-quinolyl)phenoxy]piperidine-1-carboxylate (250 mg, 0.58mmol) in ethanol (4 mL) was added 0.5 M of sodium hydroxide in H₂O (12.8mL, 6.40 mmol), followed by 30% aq. hydrogen peroxide (0.6 mL, 6 mmol).The reaction was stirred at 50° C. (24 h), but only 8-10% of desiredproduct was observed. The reaction mixture was cooled to RT andneutralized with 10% aq. H₂SO₄ and was concentrated under reducedpressure. The crude reaction mixture was re-dissolved in1-methoxy-2-propanol (10 mL). Solid sodium hydroxide (0.256 g, 6.40mmol) was added, followed by H₂O (1 mL) and 30% aq. hydrogen peroxide(0.6 ml, 6 mmol). The reaction was stirred at 98° C. (24 h) and thistime ˜40% of desired product was observed. Additional sodium hydroxide(0.256, 6.40 mmol) and 30% aq. hydrogen peroxide (0.6 ml, 6 mmol) wasadded. After additional heating at 98° C. (12 h), ˜60% of desiredproduct was observed. Additional sodium hydroxide (0.256, 6.4026 mmol)and 30% aq. hydrogen peroxide (0.6 ml, 6 mmol) was added and thereaction mixture was heated at 98° C. for additional 4 h. The reactionmixture was cooled to RT, neutralized with conc. aq. H₂SO₄ andevaporated under reduced pressure. The contents of the flask weredissolved in DMSO, the solids filtered and the resulting solution waspurified by HPLC (reverse phase, 5-52% ACN/H₂O). The combined fractionswere lyophilized to yield the desired product7-[4-(4-piperidyloxy)phenyl]quinoline-8-carboxamide;2,2,2-trifluoroacetic acid as an yellow solid (60 mg, 20%). Analysis:LCMS m/z=348 (M+1).

Step 3.7-[4-[[1-[(2R)-Tetrahydrofuran-2-carbonyl]-4-piperidyl]oxy]phenyl]quinoline-8-carboxamide

A solution of (R)-tetrahydrofuran-2-carboxylic acid (0.006 mL, 0.07mmol), HATU (26 mg, 0.068 mmol) and DIPEA (0.045 mL, 0.26 mmol) inacetonitrile (0.2 mL, 5 mmol) was stirred at room temperature for 10min. 7-[4-(4-piperidyloxy)phenyl]quinoline-8-carboxamide; TFA (30 mg,0.06 mmol) was added and the mixture was stirred at RT for 1 hour. Thereaction was quenched by addition of MeOH (1 mL). The solvent wasevaporated in vacuo. The crude product was purified by HPLC (reversephase, 5-52% ACN/H₂O). The combined aqueous fractions were diluted withsat. Na₂CO₃ (25 mL), extracted with DCM (3×30 mL) to give the desiredproduct (free base) as a white solid. The product was lyophilized togive the 7-[4-[[1-[(2R)-tetrahydrofuran-2-carbonyl]-4piperidyl]oxy]phenyl]quinoline-8-carboxamide as a white solid (25 mg,80%). Analysis: LCMS m/z=446 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.03 (dd,J=4.27, 1.76 Hz, 1H), 8.16-8.25 (m, 1H), 7.88-7.96 (m, 1H), 7.61 (s,3H), 7.43-7.49 (m, 1H), 7.00 (d, J=8.78 Hz, 2H), 5.75-5.92 (m, 2H),4.56-4.72 (m, 2H), 3.51-4.01 (m, 6H), 2.27-2.40 (m, 1H), 1.85-2.13 (m,7H).

The following compound was synthesized using the procedure for Example336:

Example 337.7-[4-(1-Propionyl-piperidin-4-yloxy)-phenyl]-quinoline-8-carboxylic acidamide

Analysis: LCMS m/z=404 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 9.03 (dd,J=4.27, 1.76 Hz, 1H), 8.17-8.26 (m, 1H), 7.90 (d, J=8.53 Hz, 1H), 7.60(dd, J=8.66, 2.38 Hz, 3H), 7.41-7.50 (m, 1H), 7.00 (d, J=8.78 Hz, 2H),5.79-5.94 (m, 2H), 4.55-4.67 (m, 1H), 3.63-3.92 (m, 3H), 3.40-3.54 (m,1H), 2.34-2.47 (m, 2H), 1.83-2.03 (m, 4H), 1.18 (t, J=7.40 Hz, 3H).

Example 338. 1-(3-(4-(Quinolin-3-yl)phenoxy)azetidin-1-yl)propan-1-one

Step 1. tert-Butyl 3-(4-bromophenoxy)azetidine-1-carboxylate

To tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (7 g, 0.027mol) and Cs₂CO₃ (10.9 g, 0.033 mol) in DMF (200 mL) was added4-bromophenol (4.82 g, 0.027 mol). The reaction was heated to 80° C. for18 h, and then cooled to RT. Ice water was added to the reaction mixturewhen a white solid tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylatewas obtained which was filtered, washed with water and dried (6.5 g,71%). Analysis: ¹H NMR (400 MHz, DMSO-d₆) δ: 7.50-7.41 (m, 2H),6.85-6.76 (m, 2H), 5.0-4.96 (m, 1H), 4.32-4.23 (m, 2H), 3.77 (m, 2H),1.38 (s, 9H); LCMS (ESI): 328 (M+1).

Step 2. tert-Butyl 3-(4-(quinolin-3-yl)phenoxy)azetidine-1-carboxylate

A solution of tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate (1.5g, 4.57 mmol), quinolin-3-boronic acid (948 mg, 5.5 mmol) and Na₂CO₃(1.2 g, 11.42 mmol) in 1,4-dioxane (60 mL) and water (15 mL) wasdegassed by argon for 15 min. Tetrakis(triphenylphosphine) palladium(0)(264 mg, 0.23 mmol) was then added under argon atmosphere and reactionmixture was heated at 100° C. for 15 h. The reaction mixture was cooledto RT and filtered through Celite pad, washed with ETOAc. Filtrate waswashed with water and brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by column chromatography(50% EtOAc-Hexane) to afford tert-butyl3-(4-(quinolin-3-yl)phenoxy)azetidine-1-carboxylate (950 mg, 55%).Analysis: LCMS (ESI): 377 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.22 (d,J=2.3 Hz, 1H), 8.58 (d, J=2.5 Hz, 1H), 8.03 (d, J=8.3 Hz, 2H), 7.84 (d,J=8.2 Hz, 2H), 7.81-7.70 (m, 1H), 7.63 (t, J=7.5 Hz, 1H), 7.02 (d, J=8.2Hz, 2H), 5.08 (m, 1H), 4.35 (t, J=7.9 Hz, 2H), 3.84 (dd, J=10.1, 4.0 Hz,2H), 1.40 (s, 9H).

Step 3. 3-(4-(Azetidin-3-yloxy)phenyl)quinoline hydrochloride

To a solution of t-butyl3-(4-(quinolin-3-yl)phenoxy)azetidine-1-carboxylate (950 mg) in DCM (20mL) was added 4M HCl in 1,4-dioxane (6 mL) at 0° C. The reaction mixturewas stirred at RT for 2 h. After completion of the reaction, it wasconcentrated under reduced pressure to afford3-(4-(azetidin-3-yloxy)phenyl)quinoline HCl (800 mg, 98%) which was usedin the next step without further purification. Analysis: LCMS (ESI): 277(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.24-9.19 (m, 1H), 8.57 (s, 1H),8.03 (d, J=8.3 Hz, 2H), 7.78 (dd, J=33.2, 8.2 Hz, 3H), 7.63 (t, J=7.6Hz, 1H), 6.99 (t, J=10.9 Hz, 2H), 5.76 (s, 1H), 5.11-5.06 (m, 1H),3.87-3.78 (m, 2H), 3.55 (t, J=7.0 Hz, 1H), 1.23 (s, 1H).

Step 4. 1-(3-(4-(Quinolin-3-yl)phenoxy)azetidin-1-yl)propan-1-one

To a stirred solution of 3-(4-(azetidin-3-yloxy)phenyl)quinoline HCl (1eq.) and Et₃N (3 eq.) in DCM was added dropwise acid chloride (1.1 eq.)at 0° C. and the reaction mixture was then stirred at room temperaturefor 2 hour. On completion of reaction, the reaction mixture was dilutedwith DCM and washed with water. Organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure. Purification by columnchromatography using silica gel and 5-6% MeOH/DCM as eluent afforded1-(3-(4-(quinolin-3-yl)phenoxy)azetidin-1-yl)propan-1-one. Analysis: mp172° C.; LCMS (ESI): 333 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.23 (d,J=2.4 Hz, 1H), 8.59 (d, J=2.4 Hz, 1H), 8.04 (d, J=8.5 Hz, 2H), 7.90-7.82(m, 2H), 7.78-7.75 (m, 1H), 7.68-7.59 (m, 1H), 7.08-6.99 (m, 2H),5.16-5.13 (m, 1H), 4.64-4.55 (m, 1H), 4.34 (dd, J=10.5, 6.5 Hz, 1H),4.12 (dd, J=9.6, 3.8 Hz, 1H), 3.81 (dd, J=10.4, 3.8 Hz, 1H), 2.19-2.04(m, 2H), 0.98 (q, J=7.5 Hz, 3H).

The following examples were prepared using the procedure to Example 338,using the requisite acid chloride in Step 4.

Example 339.2-Methyl-1-(3-(4-(quinolin-3-yl)phenoxy)azetidin-1-yl)propan-1-one

Analysis: mp 162° C.; LCMS (ESI): 347 (M+1); ¹H NMR (400 MHz, DMSO-d₆)δ: 9.23 (d, J=2.4 Hz, 1H), 8.59 (d, J=2.4 Hz, 1H), 8.04 (d, J=8.3 Hz,2H), 7.91-7.81 (m, 2H), 7.80-7.71 (m, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.04(d, J=8.5 Hz, 2H), 5.14 (m, 1H), 4.66 (dd, J=9.3, 6.4 Hz, 1H), 4.39-4.29(m, 1H), 4.16 (dd, J=9.4, 3.8 Hz, 1H), 3.81 (m, 1H), 0.99 (t, J=6.5 Hz,7H).

Example 340.Cyclopropyl(3-(4-(quinolin-3-yl)phenoxy)azetidin-1-yl)methanone

Analysis: mp 187° C.; LCMS (ESI): 345 (M+1); ¹H NMR (400 MHz, DMSO-d₆)δ: 9.23 (d, J=2.4 Hz, 1H), 8.59 (d, J=2.4 Hz, 1H), 8.04 (d, J=8.5 Hz,2H), 7.90-7.82 (m, 2H), 7.80-7.71 (m, 1H), 7.64 (t, J=7.5 Hz, 1H), 7.05(d, J=8.6 Hz, 2H), 5.19-5.17 (m, 1H), 4.75 (t, J=8.1 Hz, 1H), 4.36 (dd,J=10.5, 6.5 Hz, 1H), 4.24 (dd, J=9.7, 3.7 Hz, 1H), 3.83 (dd, J=10.9, 3.9Hz, 1H), 1.20-1.04 (m, 1H), 0.88-0.63 (m, 4H).

Example 341.3-Methyl-1-(3-(4-(quinolin-3-yl)phenoxy)azetidin-1-yl)butan-1-one

Analysis: mp 201° C.; LCMS (ESI): 361 (M+1); ¹H NMR (400 MHz, DMSO-d₆)δ: 9.23 (d, J=2.4 Hz, 1H), 8.58 (d, J=2.4 Hz, 1H), 8.03 (d, J=8.4 Hz,2H), 7.85 (d, J=8.5 Hz, 2H), 7.80-7.59 (m, 2H), 7.04 (d, J=8.3 Hz, 2H),5.15-5.12 (m, 1H), 4.60 (dd, J=9.6, 6.4 Hz, 1H), 4.34 (dd, J=10.6, 6.5Hz, 1H), 4.11 (dd, J=9.7, 3.8 Hz, 1H), 3.81 (dd, J=10.8, 3.9 Hz, 1H),2.49 (s, 1H), 1.98 (d, J=2.9 Hz, 2H), 0.96-0.79 (m, 6H).

Example 342.(S)-1-(3-(4-(Quinolin-7-yl)phenoxy)pyrrolidin-1-yl)propan-1-one, HCl

Step 1. (R)-1-(3-Hydroxypyrrolidin-1-yl)propan-1-one

To a solution of (R)-3-hydroxypyrrolidine (1.5 g, 0.017 mol) in DCM (20mL) was added triethylamine (6.6 mL, 0.051 mol) at 0° C. The reactionmixture was stirred at 0° C. for 10 minutes, when propionyl chloride(1.59 g, 0.017 mol) was added dropwise, and the mixture was stirred atroom temperature for 15 h. On completion of the reaction monitored byTLC, the reaction mixture was partitioned between DCM and water. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to obtain thecrude product which was purified by column chromatography using silicagel to afford (R)-1-(3-hydroxypyrrolidin-1-yl)propan-1-one (2.3 g, 92%)as a colorless oil. Analysis: ¹H NMR (400 MHz, CDCl₃) δ: 4.55-4.50 (m,1H), 3.69-3.37 (m, 4H), 2.74-2.64 (m, 2H), 2.36-2.16 (m, 2H), 1.14 (t,J=7.5 Hz, 3H).

Step 2. (S)-1-(3-(4-Bromophenoxy)pyrrolidin-1-yl)propan-1-one

(R)-1-(3-Hydroxypyrrolidin-1-yl)propan-1-one (2.3 g, 0.015 mol), wastaken in DCM (30 mL) to which ADDP (4.8 g, 0.019 mol) was added at rtfollowed by addition of triphenylphosphine (5.01 g, 0.019 mol).4-bromophenol (4.23 g, 0.019 mol) was then added and the reactionmixture was stirred at rt for 15 h. The reaction mixture was dilutedwith DCM and washed with 1N HCl solution, saturated NaCO₃ solutionsuccessively. Organic layer was separated, dried over Na₂SO₄, filteredand concentrated. The crude product was purified by columnchromatography (neutral alumina, 2% MeoH in DCM), to afford(S)-1-(3-(4-bromophenoxy)pyrrolidin-1-yl)propan-1-one (1.9 g, 40%) aslight yellow oil. Analysis: LCMS (ESI): 298 (M+1); ¹H NMR (400 MHz,CDCl₃) δ: 7.53-7.33 (m, 2H), 6.80-6.70 (m, 2H), 4.86 (m, 1H), 3.86-3.52(m, 4H), 2.39-2.00 (m, 4H), 1.16 (q, J=7.3 Hz, 3H).

Step 3. (S)-1-(3-(4-(Quinolin-7-yl)phenoxy)pyrrolidin-1-yl)propan-1-onehydrochloride

A solution of (S)-1-(3-(4-bromophenoxy)pyrrolidin-1-yl)propan-1-one (300mg, 1.0 mmol) in 1,4 dioxane:water (9 ml:3 ml) was added Na₂CO₃ (320 mg,3 mmol), quinolin-7-boronic acid (209 mg, 1.2 mmol) and degassed withargon for 20 min. This was followed by addition of tetrakis Pd (12 mg,0.01 mmol) and the reaction mixture was heated at 120° C. for 15 h. Thereaction mixture was cooled to RT and filter through Celite bed, thefiltrate was diluted ethyl acetate and washed with water. The organiclayer was dried over Na₂SO₄, filtered and concentrated. Crude productwas purified by column chromatography using silica gel (2-3% MeOH/DCM)to afford free base which was treated with 4M HCl in dioxane to afford(S)-1-(3-(4-(quinolin-7-yl)phenoxy)pyrrolidin-1-yl)propan-1-one HCl (110mg, 32%) as a pale yellow sticky solid. Analysis: LCMS (ESI): 347 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ: 9.22 (d, J=5.0 Hz, 1H), 9.01 (d, J=8.2 Hz,1H), 8.46 (t, J=2.5 Hz, 1H), 8.35 (d, J=8.7 Hz, 1H), 8.23 (dd, J=8.7,1.8 Hz, 1H), 7.98-7.82 (m, 3H), 7.23-7.13 (m, 2H), 5.13 (m, 1H),3.75-3.30 (m, 4H), 2.33-2.07 (m, 4H), 1.23 (d, J=3.6 Hz, 3H).

Example 343.(S)-1-(3-(4-(Quinolin-3-yl)phenoxy)pyrrolidin-1-yl)propan-1-one, HCl

This example was synthesized using the method for Example 341, usingquinolin-3-boronic acid in Step 3.

Analysis: mp 60° C.; LCMS (ESI): 347 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ:9.67-9.61 (m, 1H), 9.45-9.39 (m, 1H), 8.44 (d, J=8.5 Hz, 1H), 8.38-8.31(m, 1H), 8.1-808 (m, 1H), 8.04-7.90 (m, 3H), 7.25-7.15 (m, 2H), 5.16 (m,1H), 3.69-3.49 (m, 3H), 3.43-3.30 (m, 1H), 2.35-2.02 (m, 4H), 1.13-0.93(m, 3H).

The following examples were prepared by analogy to Examples 342 and 343,using (S)-3-hydroxypyrrolidine in Step 1.

Example 344(R)-1-(3-(4-(Quinolin-7-yl)phenoxy)pyrrolidin-1-yl)propan-1-one, HCl

Analysis: mp 53° C.; LCMS (ESI): 347 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ:8.99 (s, 1H), 8.83 (d, J=7.4 Hz, 1H), 8.15 (s, 2H), 7.87-7.75 (m, 3H),7.26 (s, 1H), 7.02 (d, J=8.2 Hz, 2H), 5.06 (s, 1H), 3.81-3.60 (m, 4H),2.40-2.31 (m, 3H), 2.23 (s, 1H), 1.28-1.15 (m, 3H).

Example 345.(R)-1-(3-(4-(quinolin-3-yl)phenoxy)pyrrolidin-1-yl)propan-1-one, HCl

Analysis: mp 51° C.; LCMS (ESI): 347 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ:9.26-9.20 (m, 1H), 8.62-8.54 (m, 1H), 8.03 (d, J=8.4 Hz, 2H), 7.93-7.68(m, 3H), 7.63 (t, J=7.6 Hz, 1H), 7.20-7.09 (m, 2H), 5.12 (t, J=3.3 Hz,1H), 3.69-3.49 (m, 2H), 3.23 (d, J=4.7 Hz, 2H), 2.33-2.03 (m, 4H), 0.99(m, 3H).

Example 346.1-(4-(4-(5-Methylquinolin-7-yl)phenoxy)piperidin-1-yl)propan-1-one, HCl

Step 1. 5-Bromo-7-methylquinoline and 7-Bromo-5-methylquinoline

To a mixture of 3-bromo-5-methylaniline (2.0 g), glycerol (2.8 eq.) andsodium-3-nitrobenzenesulphonate (1.8 eq.) in H₂O (16 ml), conc. sulfuricacid (16 ml) was added at 0° C. dropwise. The reaction mixture washeated at 140° C. for 4 days. The reaction mixture was cooled to room &poured on ice, then carefully adjusted to basic pH (pH ˜8) with aq. 20%NaOH solution. The mixture was then extracted with ethyl acetate (3×100mL). Combined organic layer were dried over Na₂SO₄ and concentrationgive crude product which was purified preparative HPLC to afford5-bromo-7-methylquinoline (240 mg) and 7-bromo-5-methylquinoline (210mg).

Step 2. tert-Butyl4-(4-(5-methylquinolin-7-yl)phenoxy)piperidine-1-carboxylate

To a degassed solution of4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (1 eq.), 5-Bromo-7-methylquinoline (1 eq.) andsodium carbonate (2.6 eq.) in dioxane/water (3:1), was addedtetrakis-(triphenylphosphino)-palladium (13 mg, 0.012 mmol) and thereaction mixture was heated at 100° C. for 15 h when TLC confirmedcompletion of reaction. The reaction was filtered through a bed ofCelite and the filtrate was diluted with ethyl acetate and washed withwater. The combined organic phases was concentrated to get the crudeproduct was purified by column chromatography using silica gel and30-40% EtOAc/hexane as eluent to afford tert-butyl4-(4-(5-methylquinolin-7-yl)phenoxy)-piperidine-1-carboxylate (64%).Analysis: LCMS (ESI): 419 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.86 (d,J=4.2 Hz, 1H), 8.15 (d, J=8.6 Hz, 1H), 7.81 (s, 1H), 7.47-7.34 (m, 4H),7.13 (d, J=8.4 Hz, 2H), 4.64 (m, 1H), 3.75-3.61 (m, 2H), 3.21 (m, 2H),2.55 (s, 3H), 1.97 (m, 2H), 1.64-1.50 (m, 2H), 1.41 (s, 9H).

Step 3. 5-Methyl-7-(4-(piperidin-4-yloxy)phenyl)quinoline

To a solution of tert-butyl4-(4-(5-methylquinolin-7-yl)phenoxy)piperidine-1-carboxylate (1 eq.) inDCM (20 mL) was added TFA (0.4 mL) at 0° C., and the reaction mixturewas then stirred for 2 h at rt. Volatiles were removed at reducedpressure. Residue was triturated with ether to afford5-methyl-7-(4-(piperidin-4-yloxy)phenyl)quinoline. Analysis: LCMS (ESI):319 (M+1)

Step 4.1-(4-(4-(5-Methylquinolin-7-yl)phenoxy)piperidin-1-yl)propan-1-one, HCl

To a solution of 5-methyl-7-(4-(piperidin-4-yloxy)phenyl)quinoline (1eq.) in DCM (20 mL) was added at 0° C., Et₃N (3 eq.) and propanoylchloride (1 eq.) and the reaction mixture was stirred for 3 h at rt. Oncompletion of reaction, the reaction mixture was diluted with DCM andwashed with water. The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated. The crude product was purified bycolumn chromatography using silica gel and 2-3% MeOH/DCM as eluent. Thepurified free base was converted to the hydrochloride salt by treatmentwith 4M HCl in dioxane, followed by trituration in ethyl acetate:hexane,filtration and drying in vacuo to afford1-(4-(4-(5-methylquinolin-7-yl)phenoxy)piperidin-1-yl)propan-1-one HCl.Analysis: LCMS (ESI): 375 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.91 (d,J=4.2 Hz, 1H), 8.45 (d, J=8.4 Hz, 1H), 8.08 (s, 1H), 7.84-7.75 (m, 3H),7.53 (m, 1H), 7.14 (d, J=8.4 Hz, 2H), 4.71 (m, 1H), 3.95-3.84 (m, 1H),3.77-3.66 (m, 1H), 3.37 (m, 1H), 3.26 (m, 1H), 2.73 (s, 3H), 2.35 (q,J=7.4 Hz, 2H), 2.05-1.88 (m, 2H), 1.62 (m, 1H), 1.56 (m, 1H), 1.00 (t,J=7.4 Hz, 3H).

The following examples were prepared by analogy to Example 346, usingthe requisite heteroaryl bromide in Step b and acid chloride in Step dor with (R)-tetrahydrofuran-2-carboxylic acid in the presence of EDCIand HOBT for Step 4.

Example 347.Cyclopropyl(4-(4-(5-methylquinolin-7-yl)phenoxy)piperidin-1-yl)methanone,HCl

Analysis: LCMS (ESI): 387 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.19 (d,J=5.0 Hz, 1H), 9.03 (d, J=8.4 Hz, 1H), 8.30 (s, 1H), 8.08 (s, 1H),7.95-7.80 (m, 3H), 7.20 (d, J=8.8 Hz, 2H), 4.77 (m, 1H), 3.99 (m, 1H),3.89 (m, 1H), 3.59 (m, 1H), 3.34 (m, 1H), 2.82 (s, 3H), 2.03 (m, 3H),1.66 (m, 1H), 1.54 (m, 1H), 0.72 (m, 4H).

Example 348.1-(4-(4-(7-methylquinolin-5-yl)phenoxy)piperidin-1-yl)propan-1-one HCl

Analysis: LCMS (ESI): 375 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.23 (d,J=5.2 Hz, 1H), 8.85 (d, J=8.6 Hz, 1H), 8.14 (s, 1H), 7.94 (m, 1H), 7.74(s, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 4.75 (m, 1H),3.91 (m, 1H), 3.78-3.65 (m, 1H), 3.44-3.21 (m, 2H), 2.67 (s, 3H), 2.36(q, J=7.4 Hz, 2H), 2.04-1.93 (m, 2H), 1.61 (m, 1H), 1.56 (m, 1H), 1.00(t, J=7.4 Hz, 3H).

Example 349.Cyclopropyl-{4-[4-(7-methyl-quinolin-5-yl)-phenoxy]-piperidin-1-yl}-methanone,HCl

Analysis: LCMS (ESI): 387 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.19 (d,J=5.0 Hz, 1H), 8.76 (d, J=8.5 Hz, 1H), 8.08 (s, 1H), 7.87 (m, 1H), 7.69(s, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 4.77 (m, 1H),4.01 (m, 1H), 3.91 (m, 1H), 3.60 (m, 1H), 3.31 (m, 1H), 2.66 (s, 3H),2.09-1.94 (m, 3H), 1.68 (m, 1H), 1.57 (m, 1H), 0.79-0.66 (m, 4H).

Example 350.1-(4-(4-(6-Methylquinolin-5-yl)phenoxy)piperidin-1-yl)propan-1-one HCl

Analysis: LCMS (ESI): 375 (M+1); ¹H NMR (400 MHz, DMSO-d6) δ: 8.82 (d,J=4.3 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.72 (m, 2H), 7.41 (m, 1H), 7.17(d, J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 4.71 (m, 1H), 3.95 (m, 1H),3.75 (m, 1H), 3.37 (m, 1H), 3.24 (m, 1H), 2.36 (q, J=7.4 Hz, 2H), 2.24(s, 3H), 2.02 (m, 2H), 1.66 (m, 1H), 1.55 (m, 1H), 0.99 (q, J=7.4 Hz,3H).

Example 351.Cyclopropyl(4-(4-(6-methylquinolin-5-yl)phenoxy)piperidin-1-yl)methanone,HCl

Analysis: LCMS (ESI): 387 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.14 (d,J=4.9 Hz, 1H), 8.26 (m, 2H), 8.03 (d, J=8.8 Hz, 1H), 7.82 (m, 1H), 7.25(d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 4.75 (m, 1H), 4.03 (m, 1H),3.95 (m, 1H), 3.56 (m, 1H), 3.29 (m, 1H), 2.32 (s, 3H), 2.08-1.96 (m,3H), 1.69 (s, 1H), 1.58 (s, 1H), 0.73 (m, 4H).

Example 352.(R)-(4-(4-(5-Methylquinolin-7-yl)phenoxy)piperidin-1-yl)(tetrahydrofuran-2-yl)methanone

Analysis: LCMS (ESI): 417 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.91 (d,J=4.2 Hz, 1H), 8.45 (m, 1H), 8.05 (s, 1H), 7.80 (m, 3H), 7.53 (m, 1H),7.14 (d, J=8.6 Hz, 2H), 4.77-4.65 (m, 2H), 3.78 (m, 4H), 3.51 (m, 1H),3.30 (m, 1H), 2.73 (s, 3H), 2.13-1.75 (m, 6H), 1.65-1.49 (m, 2H).

Example 353.(R)-(4-(4-(7-Methylquinolin-5-yl)phenoxy)piperidin-1-yl)(tetrahydrofuran-2-yl)methanone

Analysis: LCMS (ESI): 417 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.86 (d,J=4.2 Hz, 1H), 8.15 (m, 1H), 7.82 (s, 1H), 7.48-7.35 (m, 4H), 7.15 (d,J=8.4 Hz, 2H), 4.77-4.65 (m, 2H), 3.96-3.69 (m, 4H), 3.51 (m, 1H), 3.21(m, 1H), 2.56 (s, 3H), 2.13-1.74 (m, 6H), 1.73-1.51 (m, 2H).

Example 354.(R)-(4-(4-(6-Methylquinolin-5-yl)phenoxy)piperidin-1-yl)(tetrahydrofuran-2-yl)methanone

Analysis: LCMS (ESI): 417 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.82 (d,J=4.1 Hz, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.76-7.68 (m, 2H), 7.41 (m, 1H),7.18 (m, 4H), 4.71 (m, 2H), 4.01-3.70 (m, 4H), 3.50 (m, 1H), 3.21 (m,1H), 2.25 (s, 3H), 2.12-2.01 (m, 4H), 1.95-1.76 (m, 2H), 1.72-1.52 (m,2H).

Example 355.(±)-(7S,8aS)-7-(4-(8-Methylquinolin-7-yl)phenoxy)hexahydroindolizin-3(2H)-one

Step 1. 7-(4-Fluorophenyl)-8-methylquinoline

A solution of 7-bromo-8-methylquinoline (1.0 g, 4.52 mmol),4-fluorophenyl-boronic acid (0.74 g, 5.36 mmol) and Na₂CO₃ (1.62 g, 15.3mmol) in 1,4-dioxane (20 mL) and water (4 mL) was degassed by argon for30 min tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.22 mmol) wasadded and reaction mixture was heated at 100° C. for 15 h. The reactionmixture was cooled to RT and filtered through Celite pad, washed withethyl acetate. Filtrate was washed with water and brine, dried overNa₂SO₄, filtered and concentrated. Purification was carried out bycolumn chromatography to afford 7-(4-fluorophenyl)-8-methylquinoline(0.99 g, 92%). Analysis: LCMS (ESI): 238 (M+1); ¹H NMR (400 MHz, CDCl₃)δ: 9.00 (dd, J=4.2, 1.9 Hz, 1H), 8.17 (dd, J=8.2, 1.9 Hz, 1H), 7.71 (d,J=8.4 Hz, 1H), 7.41-7.39 (m, 4H), 7.22-7.11 (m, 2H), 2.74 (s, 3H).

Step 2.(±)-(7S,8aS)-7-(4-(8-methylquinolin-7-yl)phenoxy)hexahydroindolizin-3(2H)-one

To a solution of (±)-(7S,8aS)-7-hydroxyhexahydroindolizin-3(2H)-one(0.25 g, 1.61 mmol) (prepared according to Schoemaker, H. E. et al,Tetrahedron, 1978, 34, 163-172) in NMP, cooled at 0° C., was added NaH(60% in oil, 0.077 g, 1.93 mmol) and stirred at 0° C. for 30 min. Tothis solution 7-(4-fluorophenyl)-8-methylquinoline (0.4 g, 1.69 mmol) inNMP was added in dropwise fashion followed by heating at 100° C. for 12h. The reaction mixture was quenched with water and extracted with ethylacetate. The organic layer again washed with water, brine, was driedover Na₂SO₄ and concentrated. Residue was purified by columnchromatography (silica, 3-5% methanol in DCM to afford(±)-(7S,8aS)-7-(4-(8-methylquinolin-7-yl)phenoxy)hexahydroindolizin-3(2H)-one(0.11 g, 18%). -LCMS (ESI): 373 (M+1); ¹H NMR (400 MHz, CDCL₃) δ:9.02-8.96 (m, 1H), 8.16 (dd, J=8.3, 1.9 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H),7.54-7.31 (m, 4H), 7.01 (dd, J=8.6, 2.5 Hz, 2H), 4.45-4.41 (m, 1H),4.29-4.27 (m, 1H), 3.69-3.57 (m, 1H), 2.87-2.72 (m, 4H), 2.45 (s, 3H),2.3-2.28 (m, 2H), 1.78-1.56 (m, 2H), 1.45-1.42 (m, 1H).

Example 356.(±)-(7R,8aS)-7-(4-(8-Methylquinolin-7-yl)phenoxy)hexahydroindolizin-3(2H)-one

Step 1. 4-(8-Methylquinolin-7-yl)-phenol

A solution of 7-bromo-8-methylquinoline (1.0 g, 4.52 mmol),4-hydroxyphenyl-boronic acid (0.76 g, 5.41 mmol) and Na₂CO₃ (1.62 g,15.3 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was degassed by argonfor 30 min tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.22 mmol)was added and reaction mixture was heated at 100° C. for 15 h. Thereaction mixture was cooled to rt and filtered through Celite pad,washed with ethyl acetate. Filtrate was washed with water and brine,dried over Na₂SO₄, filtered and concentrated. Purification was carriedout by column chromatography to afford 4-(8-methylquinolin-7-yl)-phenol(1.0 g, 93%). Analysis: LCMS (ESI): 236 (M+1); ¹H NMR (400 MHz, DMSO-d₆)δ: 9.57 (s, 1H), 8.96 (dd, J=4.2, 1.8 Hz, 1H), 8.35 (dd, J=8.2, 1.8 Hz,1H), 7.83 (d, J=8.4 Hz, 1H), 7.53 (dd, J=8.2, 4.2 Hz, 1H), 7.45 (d,J=8.4 Hz, 1H), 7.30-7.20 (m, 2H), 6.93-6.84 (m, 2H), 2.67 (s, 3H).

Step 2.(±)-(7R,8aS)-7-(4-(8-methylquinolin-7-yl)phenoxy)hexahydroindolizin-3(2H)-one

To a solution of (±)-(7S,8aS)-7-hydroxyhexahydroindolizin-3(2H)-one (0.4g, 2.58 mmol) and 4-(8-methylquinolin-7-yl)-phenol (0.63 g, 2.70 mmol)in THF, cooled at 0° C., was added triphenylphosphine (0.87 g, 3.35mmol) and stirred at 0° C. for 20 min. To this solution was addeddi-tert-butyl azodicarboxylate (0.77 g, 3.35 mmol) followed by stirringat rt for 12 h. The reaction mixture was concentrated under reducedpressure. Residue was purified by column chromatography (silica, 1-2%methanol in DCM) to afford(±)-(7R,8aS)-7-(4-(8-methylquinolin-7-yl)phenoxy)hexahydroindolizin-3(2H)-one(0.12 g, 13%). Analysis: LCMS (ESI): 373 (M+1); ¹H NMR (400 MHz, CDCl₃)δ: 9.00 (dd, J=4.1, 1.8 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 7.70 (d, J=8.4Hz, 1H), 7.50-7.27 (m, 4H), 7.02 (dd, J=8.7, 3.0 Hz, 2H), 4.83 (d, J=3.4Hz, 1H), 4.11-3.91 (m, 2H), 3.18-3.16 (m, 1H), 2.78 (s, 3H), 2.49-2.17(m, 4H), 2.14 (d, J=14.3 Hz, 1H), 1.76-1.56 (m, 2H), 1.47-1.45 (m, 1H).

Example 357.2,2,2-Trifluoro-1-{4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-ethanone

Step 1. 4-[4-(8-Methylquinolin-7-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester

4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (1.01 g, 2.51 mmol), 7-bromo-8-methylquinoline(0.556 g, 2.50 mmol), tetrakis(triphenylphosphine)palladium(0) (0.123 g,0.106 mmol) and K₂CO₃ (0.556 g, 4.02 mmol) were combined in water (6.0mL): 1,4-dioxane (24.0 mL). The mixture was briefly vacuum degassed thenstirred at 80° C. under an atmosphere of nitrogen overnight. The mixturewas cooled, partitioned between EtOAc (100 mL) and water (20 mL) and thelayers wee separated. The aqueous layer was extracted with EtOAc (50 mL)and the combined organics were washed with brine (50 mL), dried oversodium sulfate and filtered through 2 mL silica gel. The filtrate wasconcentrated in vacuo to afford4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester.

Step 2. 8-Methyl-7-[4-(piperidin-4-yloxy)-phenyl]-quinolinedihydrochloride

Crude 4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester was dissolved in methanol (10.0 mL, 247 mmol) and4.0 M of HCl in 1,4-dioxane (3.00 mL, 12.0 mmol) was added. Afterstirring overnight, the mixture was diluted with ethyl acetate:hexanes(1:1, 60 mL) and the resultant solids were collected by filtration,washed with ethyl acetate:hexanes (1:1, 10 mL) then dried in vacuo toafford 8-methyl-7-[4-(piperidin-4-yloxy)-phenyl]-quinolinedihydrochloride (0.830 g; 84.7%). Analysis: ¹H NMR (400 MHz, DMSO-d₆) δ:8.94-9.34 (3H, m), 8.62-8.94 (1H, m), 8.06 (1H, d, J=8.5 Hz), 7.73-7.87(1H, m), 7.66 (1H, d, J=8.3 Hz), 7.43 (2H, d, J=8.8 Hz), 7.17 (2H, d,J=8.8 Hz), 4.60-5.00 (1H, m), 3.18-3.34 (2H, m), 2.99-3.15 (2H, m), 2.72(3H, s), 2.10-2.23 (2H, m), 1.74-1.98 (2H, m).

Step 3.2,2,2-Trifluoro-1-{4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidin-1-yl}-ethanone

Trifluoroacetic anhydride (67.7 uL, 0.479 mmol) was added to8-methyl-7-[4-(piperidin-4-yloxy)-phenyl]-quinoline 2HCl (0.125 g, 0.319mmol) and DIPEA (0.250 mL, 1.44 mmol) in DMF (3.00 mL). After 2 h, themixture was concentrated in vacuo. The residue was dissolved in DCM,applied to a silica gel loading cartridge (5 g) and purified on silicagel (24 g, 0-5% methanol:DCM) to afford2,2,2-trifluoro-1-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-ethanone(92 mg, 69%) after reconcentration from ether. Analysis: LCMS (ESI): 415(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.97 (1H, dd, J=4.3, 1.8 Hz), 8.37(1H, dd, J=8.3, 1.8 Hz), 7.86 (1H, d, J=8.3 Hz), 7.55 (1H, dd, J=8.2,4.1 Hz), 7.48 (1H, d, J=8.5 Hz), 7.39 (2H, d, J=7.6 Hz), 7.13 (2H, d,J=7.4 Hz), 4.68-4.84 (1H, m), 3.72-3.93 (2H, m), 3.47-3.66 (2H, m), 2.68(3H, s), 1.99-2.15 (2H, m), 1.68-1.82 (2H, m); ¹⁹F NMR (377 MHz,DMSO-d₆) δ −68.07 (3F, s).

Example 358.2,2-Difluoro-1-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,HCl

2,2-Difluoropropionic acid (0.0527 g, 0.479 mmol) in DMF (1.00 mL, 12.9mmol) was added to 8-methyl-7-[4-(piperidin-4-yloxy)-phenyl]-quinoline2HCl (0.125 g, 0.319 mmol) and DIPEA (0.250 mL, 1.44 mmol) in DMF (3.0mL), then treated with HATU (0.146 g, 0.37 mmol). After 2 h, the mixturewas concentrated in vacuo. The residue was dissolved in DCM, applied toa silica gel loading cartridge (5 g) and purified on silica gel (24 g,0-5% methanol:DCM) to afford2,2-difluoro-1-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-oneHCl (83 mg, 58%) after treatment of product fractions redissolved inmethanol with 2M HCl in ether, reconcentrating from ether. Analysis:LCMS (ESI): 411 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.10 (1H, dd, J=4.5,1.5 Hz), 8.74 (1H, br. s.), 8.03 (1H, d, J=8.5 Hz), 7.79 (1H, dd, J=7.4,4.6 Hz), 7.64 (1H, d, J=8.5 Hz), 7.41 (2H, d, J=8.8 Hz), 7.15 (2H, d,J=8.8 Hz), 4.74-4.84 (1H, m), 3.89 (2H, br. s.), 3.51-3.67 (1H, m), 3.46(1H, t, J=9.3 Hz), 2.71 (3H, s), 2.04 (2H, br. s.), 1.83 (3H, t, J=20.1Hz), 1.61-1.76 (2H, m); ¹⁹F NMR (377 MHz, DMSO-d6) δ −91.22 (d, J=27.2Hz).

Example 359.2-Fluoro-1-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,HCl

Prepared by analogy with Example 358. Analysis: LCMS (ESI): 393 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ: 9.04 (1H, dd, J=4.4, 1.4 Hz), 8.59 (1H, d,J=6.5 Hz), 7.96 (1H, d, J=8.3 Hz), 7.65-7.78 (1H, m), 7.58 (1H, d, J=8.5Hz), 7.31-7.45 (2H, m), 7.14 (2H, d, J=8.8 Hz), 5.56 (1H, dq, J=47.7,6.5 Hz), 4.74 (1H, d, J=3.3 Hz), 3.91 (2H, m), 3.24-3.49 (2H, m), 2.69(3H, s), 2.02 (2H, m), 1.64 (2H, m), 1.42 (3H, dd, J=24.9, 6.5 Hz).

Example 360.{exo-3-[4-(8-Methylquinolin-7-yl)-phenoxy]-8-aza-bicyclo[3.2.1]oct-8-yl}-(R)-tetrahydrofuran-2-yl-methanone,HCl

Step 1.exo-3-[4-(8-Methyl-quinolin-7-yl)-phenoxy]-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

exo-3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butylester (379 mg, 1.67 mmol) and NaH, 60% dispersion in mineral oil (101mg, 2.52 mmol) were combined in N-methylpyrrolidinone (NMP) (4.00 mL).After 20 min, a solution of 7-(4-fluoro-phenyl)-8-methyl-quinoline (294mg, 1.24 mmol) in NMP (1.5 mL) was added and the mixture was heated at100° C. for 48 h, at which point conversion had reached ca. 50% asdetermined by LCMS. The mixture was cooled, diluted with ethyl acetate(75 mL) and hexanes (25 mL) then washed with water (3×10 mL) and brine(30 mL), dried over sodium sulfate, filtered and concentrated in vacuo.The residue was dissolved in DCM, applied to a silica gel loadingcartridge (5 g) and purified on silica gel (40 g, 0-40% ethyl acetate:hexane) to affordexo-3-[4-(8-methyl-quinolin-7-yl)-phenoxy]-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (0.192 g, 34.8%). Analysis: ¹H NMR (400 MHz,methanol-d₄) δ: 8.89 (dd, J=4.3, 2.0 Hz, 1H) 8.32 (dd, J=8.3, 1.8 Hz,1H) 7.79 (d, J=8.5 Hz, 1H) 7.51 (dd, J=8.3, 4.3 Hz, 1H) 7.47 (d, J=8.3Hz, 1H) 7.32 (d, J=8.8 Hz, 2H) 7.07 (d, J=8.8 Hz, 2H) 4.86-4.95 (m, 1H)4.25-4.32 (m, 2H) 2.68 (s, 3H) 2.17-2.26 (m, 2H) 2.01-2.08 (m, 2H)1.83-1.93 (m, 2H) 1.66-1.79 (m, 2H) 1.51 (s, 9H).

Step 2.7-{4-[exo-(8-Aza-bicyclo[3.2.1]oct-3-yl)oxy]-phenyl}-8-methyl-quinoline,2HCL

exo-3-[4-(8-Methylquinolin-7-yl)-phenoxy]-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (0.192 g, 0.432 mmol) and 4.0 M of HCl in1,4-dioxane (0.450 mL, 1.80 mmol) were combined in methanol (7.0 mL) andstirred at room temp. After 22 h, the mixture was concentrated in vacuoto afford7-{4-[exo-(8-aza-bicyclo[3.2.1]oct-3-yl)oxy]-phenyl}-8-methyl-quinoline2HCl (0.180 g, 99.8%).

Step 3.{exo-3-[4-(8-Methylquinolin-7-yl)-phenoxy]-8-aza-bicyclo[3.2.1]oct-8-yl}-(R)-tetrahydrofuran-2-yl-methanone,HCl

7-{4-[exo-(8-Aza-bicyclo[3.2.1]oct-3-yl)oxy]-phenyl}-8-methylquinoline2HCl (90.0 mg, 0.216 mmol), (R)-tetrahydrofuran-2-carboxylic acid (28.8mg, 0.248 mmol) and DIPEA (0.225 mL, 1.29 mmol) were combined in DCM(3.0 mL) and HATU (102 mg, 0.270 mmol) was added. After 2 h, the mixturewas diluted with EtOAc (20 mL), washed with saturated NaHCO₃ (5 mL) andbrine (5 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was dissolved in DCM, applied to a silica gel loading cartridge(5 g) and purified on silica gel (12 g, 10-70% ethyl acetate: hexane) toafford purified free base after concentration of product containingfractions. The free base was dissolved in methanol and treated with 4MHCl in dioxane then concentrated to afford{exo-3-[4-(8-methylquinolin-7-yl)-phenoxy]-8-aza-bicyclo[3.2.1]oct-8-yl}-(R)-tetrahydrofuran-2-yl-methanoneHCl (95 mg, 92%). Analysis: LCMS (ESI): 443 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ: 9.04 (d, J=3.0 Hz, 1H) 8.50-8.68 (m, 1H) 7.96 (d, J=8.3 Hz,1H) 7.64-7.76 (m, 1H) 7.57 (d, J=8.5 Hz, 1H) 7.37 (d, J=8.8 Hz, 2H) 7.13(d, J=8.5 Hz, 2H) 4.87-4.99 (m, 1H) 4.46-4.63 (m, 3H) 3.72-3.92 (m, 2H)2.69 (s, 3H) 2.14-2.31 (m, 2H) 1.79-2.10 (m, 8H) 1.66-1.79 (m, 1H)1.53-1.63 (m, 1H).

Example 361.1-{exo-3-[4-(8-Methylquinolin-7-yl)-phenoxy]-8-aza-bicyclo[3.2.1]oct-8-yl})-propan-1-oneHCl

7-{4-[exo-(8-Aza-bicyclo[3.2.1]oct-3-yl)oxy]-phenyl}-8-methylquinoline2HCl (90.0 mg, 0.216 mmol), and DIPEA (0.225 mL, 1.29 mmol) werecombined in DCM (3.0 mL) and propanoyl chloride (22.9 mg, 0.248 mmol)was added. After 2 h, the mixture was diluted with ethyl acetate (20mL), washed with saturated NaHCO₃ (5 mL) and brine (5 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was dissolved inDCM, applied to a silica gel loading cartridge (5 g) and purified onsilica gel (12 g, 10-60% ethyl acetate:hexane) to afford purified freebase after concentration of product containing fractions. The free basewas dissolved in methanol and treated with 4M HCl in dioxane thenconcentrated to afford1-{exo-3-[4-(8-methylquinolin-7-yl)-phenoxy]-8-aza-bicyclo[3.2.1]oct-8-yl}-propan-1-oneHCl (74 mg, 78%). Analysis: LCMS (ESI): 401 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ: 9.10 (d, J=3.3 Hz, 1H) 8.68-8.84 (m, 1H) 8.04 (d, J=8.5 Hz,1H) 7.75-7.86 (m, 1H) 7.64 (d, J=8.3 Hz, 1H) 7.38 (d, J=8.8 Hz, 2H) 7.14(d, J=8.8 Hz, 2H) 4.93-4.98 (m, 1H) 4.53-4.58 (m, 1H) 4.31-4.37 (m, 1H)2.70 (s, 3H) 2.13-2.44 (m, 4H) 1.79-2.03 (m, 4H) 1.50-1.62 (m, 2H) 1.02(t, J=7.4 Hz, 3H).

Example 362.{2-Methyl-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone,HCl

Prepared as a mixture of four diastereomers, analogous to Example 360,using 4-hydroxy-2-methyl-piperidine-1-carboxylic acid tert-butyl esterin Step 1. Analysis: LCMS (ESI): 443 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ:9.08-9.16 (m, 1H) 8.75-8.89 (m, 1H) 8.02-8.15 (m, 1H) 7.80-7.93 (m, 1H)7.64-7.73 (m, 1H) 7.37-7.47 (m, 2H) 7.07-7.19 (m, 2H) 4.84-4.92 (m, 1H)4.57-4.76 (m, 2H) 3.71-3.84 (m, 2H) 2.66-2.76 (m, 9H) 1.76-2.19 (m, 6H)1.13-1.47 (m, 3H).

Example 363.1-{2-Methyl-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,HCl

Prepared as a 1:1 mixture of diastereomers, analogous to Example 361,using 4-hydroxy-2-methyl-piperidine-1-carboxylic acid tert-butyl esterand propanoyl chloride. Analysis: LCMS (ESI): 389 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ: 9.01-9.12 (m, 1H) 8.58-8.78 (m, 1H) 7.94-8.08 (m, 1H)7.68-7.84 (m, 1H) 7.56-7.67 (m, 1H) 7.34-7.47 (m, 2H) 7.06-7.18 (m, 2H)4.78-4.94 (m, 1H) 4.30-4.52 (m, 1H) 3.64-3.73 (m, 1H) 3.28-3.52 (m, 1H)2.67-2.73 (m, 3H) 2.29-2.39 (m, 1H) 1.87-2.22 (m, 2H) 1.16-1.36 (m, 3H)0.95-1.07 (m, 3H).

Example 364.1-{2-Methyl-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,HCl

Prepared as a 1:9 mixture of diastereomers, enriched in the more polardiastereo-mer, analogous to Example 361, using4-hydroxy-2-methyl-piperidine-1-carboxylic acid tert-butyl ester andpropanoyl chloride. Analysis: LCMS (ESI): 389 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ: 9.01-9.12 (m, 1H) 8.58-8.78 (m, 1H) 7.94-8.08 (m, 1H)7.68-7.84 (m, 1H) 7.56-7.67 (m, 1H) 7.34-7.47 (m, 2H) 7.06-7.18 (m, 2H)4.78-4.94 (m, 1H) 4.30-4.52 (m, 1H) 3.64-3.73 (m, 1H) 3.28-3.52 (m, 1H)2.67-2.73 (m, 3H) 2.29-2.39 (m, 1H) 1.87-2.22 (m, 2H) 1.16-1.36 (m, 3H)0.95-1.07 (m, 3H).

Example 365.Cyclopropyl-{2-methyl-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanoneHCl

Prepared as a racemic mixture of diastereomers, analogously to Example361, using 4-hydroxy-2-methyl-piperidine-1-carboxylic acid tert-butylester and cyclopropyl carbonyl chloride. Analysis: LCMS (ESI): 401(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.00-9.10 (m, 1H) 8.55-8.70 (m, 1H)7.92-8.05 (m, 1H) 7.66-7.78 (m, 1H) 7.56-7.67 (m, 1H) 7.35-7.46 (m, 2H)7.06-7.19 (m, 2H) 4.84-4.91 (m, 1H) 4.57-4.69 (m, 1H) 4.13-4.22 (m, 1H)3.63-3.75 (m, 1H) 2.70 (s, 3H) 1.68-2.27 (m, 5H) 1.20-1.41 (m, 3H)0.64-0.82 (m, 4H).

Example 366.{cis-3-Fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanoneHCl

Step 1.cis-3-Fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester

Di-t-butyl azodicarboxylate (0.405 g, 1.76 mmol) was added to a −10 OCsolution of 4-(8-methyl-quinolin-7-yl)-phenol (0.267 g, 1.13 mmol),trans-3-Fluoro-4-hydroxy-piperidine-1-carboxylic acid t-butyl ester(0.387 g, 1.76 mmol), and triphenylphosphine (0.461 g, 1.76 mmol) in THF(12.0 mL). The mixture was allowed to slowly warm in the cooling baththen stirred overnight under an atmosphere of nitrogen. The mixture washeated at 60° C. for 24 h, resulting in significant conversion toproduct. The mixture was cooled and concentrated in vacuo onto silicagel (5 g) and purified on silica gel (80 g, 5-35% ethyl acetate:hexane)to affordcis-3-fluoro-4-[4-(8-methyl-quinolin-7-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (0.409 g, 82.6%). Analysis: LCMS (ESI): 437 (M+1);¹H NMR (400 MHz, methanol-d₄) δ 8.90 (dd, J=4.3, 1.8 Hz, 1H) 8.32 (dd,J=8.2, 1.9 Hz, 1H) 7.79 (d, J=8.5 Hz, 1H) 7.52 (dd, J=8.3, 4.3 Hz, 1H)7.48 (d, J=8.3 Hz, 1H) 7.35 (d, J=8.8 Hz, 2H) 7.13 (d, J=8.5 Hz, 2H)4.59-4.75 (m, 1H) 4.15-4.25 (m, 1H) 3.92-4.03 (m, 1H) 3.56-3.83 (m, 1H)3.34-3.44 (m, 1H) 3.17-3.25 (m, 1H) 2.69 (s, 3H) 1.84-1.98 (m, 2H) 1.45(s, 9H);

Step 2. 7-[4-(cis-3-Fluoropiperidin-4-yloxy)-phenyl]-8-methylquinoline2HCl

cis-3-Fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.495 g, 1.13 mmol) and 4.0 M of HCl in 1,4-dioxane(3.0 mL, 12 mmol) were combined in methanol (10.0 mL) and aged at roomtemperature for 3 h. The mixture was concentrated in vacuo to afford7-[4-(cis-3-fluoro-piperidin-4-yloxy)-phenyl]-8-methyl-quinoline 2HCl(0.449 g, 96.7%). Analysis: ¹H NMR (400 MHz, methanol-d4) δ 9.21 (d,J=8.3 Hz, 1H) 9.17 (dd, J=5.5, 1.5 Hz, 1H) 8.23 (d, J=8.5 Hz, 1H) 8.11(dd, J=8.2, 5.6 Hz, 1H) 7.88 (d, J=8.5 Hz, 1H) 7.47 (d, J=8.8 Hz, 2H)7.25 (d, J=8.8 Hz, 2H) 5.15-5.35 (m, 1H) 4.87-4.98 (m, 1H) 3.69-3.86 (m,1H) 3.39-3.57 (m, 3H) 2.78 (s, 3H) 2.23-2.35 (m, 2H); ¹⁹F NMR (377 MHz,methanol-d4) δ −192.91 (s, 1 F).

Step 3.{cis-3-Fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanoneHCl

(R)-Tetrahydrofuran-2-carboxylic acid (47.4 mg, 0.408 mmol) HATU (168mg, 0.443 mmol) were combined in DCM (1.6 mL, 24.8 mmol) and stirred for30 min. A solution of7-[4-(cis-3-fluoro-piperidin-4-yloxy)-phenyl]-8-methyl-quinoline 2HCl(148 mg, 0.362 mmol) and DIPEA (0.309 mL, 1.77 mmol) in DCM (4.8 mL) wasthen added. After stirring for 2 h, the mixture was diluted with ethylacetate (15 mL) and satd. aq. NaHCO₃ (7 mL). The layers were separated,the aq. extracted with EtOAc (5 mL) and the combined organics were driedover sodium sulfate, filtered and concentrated. The residue wasdissolved in DCM, applied to a silica gel loading cartridge (5 g) andpurified on silica gel (24 g, 10-80% EtOAc:hexane) to afford{cis-3-fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanoneHCl (0.131 g, 76.9%) as a 1:1 mixture of diastereomers, R-THF with 3R,4Spiperidine and R-THF with 3S,4R piperidine after treatment of productcontaining fractions with 4.0 M of HCl in 1,4-dioxane (0.355 mL, 1.42mmol) and reconcentration from methanol. Analysis: LCMS (ESI): 435(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.06-9.17 (m, 1H) 8.70-8.96 (m, 1H)7.99-8.11 (m, 1H) 7.76-7.88 (m, 1H) 7.61-7.70 (m, 1H) 7.40-7.49 (m, 2H)7.14-7.27 (m, 2H) 4.91-5.14 (m, 1H) 4.79-4.90 (m, 1H) 4.62-4.76 (m, 1H)3.93-4.55 (m, 2H) 3.59-3.84 (m, 3H) 2.71 (s, 3H) 1.93-2.11 (m, 3H)1.72-1.85 (m, 2H) 1.21-1.33 (m, 4H); ¹⁹F NMR (377 MHz, DMSO-d6) δ −69.2(s, 1F) and −71.1 (s, 1F).

The following examples were prepared by analogy with propanoyl chlorideor cyclopropyl carbonyl chloride in Step c as required and the requisiteN-Boc-piperidin-4-ol derivative.

Example 367.1-{cis-3-Fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,HCl

Analysis: LCMS (ESI): 393 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.02-9.10(m, 1H) 8.59-8.69 (m, 1H) 7.95-8.03 (m, 1H) 7.70-7.77 (m, 1H) 7.55-7.64(m, 1H) 7.37-7.45 (m, 2H) 7.13-7.22 (m, 2H) 4.90-5.13 (m, 1H) 4.77-4.88(m, 1H) 4.47-4.54 (m, 1H) 4.29-4.37 (m, 1H) 4.09-4.19 (m, 1H) 3.66-3.91(m, 1H) 3.42-3.57 (m, 1H) 3.12-3.34 (m, 1H) 2.28-2.43 (m, 2H) 1.89-1.97(m, 1H) 0.95-1.06 (m, 3H).

Example 368.Cyclopropyl-{cis-3-fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone,HCl

Analysis: LCMS (ESI): 405 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.00-9.10(m, 1H) 8.58-8.67 (m, 1H) 7.98 (d, J=8.3 Hz, 1H) 7.68-7.76 (m, 1H) 7.59(d, J=8.5 Hz, 1H) 7.42 (d, J=8.8 Hz, 2H) 7.19 (d, J=8.8 Hz, 2H)4.93-5.15 (m, 1H) 4.78-4.90 (m, 1H) 4.44-4.55 (m, 1H) 4.21-4.35 (m, 1H)3.37-3.52 (m, 1H) 2.70 (s, 3H) 1.93-2.07 (m, 2H) 1.66-1.81 (m, 1H)0.67-0.80 (m, 5H).

Example 369.1-{endo-3-[4-(8-Methylquinolin-7-yl)-phenoxy]-8-aza-bicyclo[3.2.1]oct-8-yl}-propan-1-one,HCl

Analysis: From exo-3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester. LCMS (ESI): 401 (M+1); ¹H NMR (400 MHz, DMSO-d₆)δ: 9.09 (dd, J=4.5, 1.3 Hz, 1H) 8.63-8.79 (m, 1H) 8.02 (d, J=8.5 Hz, 1H)7.72-7.82 (m, 1H) 7.64 (d, J=8.3 Hz, 1H) 7.42 (d, J=8.8 Hz, 2H) 7.04 (d,J=8.8 Hz, 2H) 4.76-4.84 (m, 1H) 4.47-4.53 (m, 1H) 4.25-4.31 (m, 1H) 2.71(s, 3H) 1.77-2.43 (m, 10H) 1.02 (t, J=7.4 Hz, 3H).

Example 370.Cyclopropyl-{endo-3-[4-(8-methylquinolin-7-yl)-phenoxy]-8-aza-bicyclo[3.2.1]oct-8-yl}-methanone,HCl

Analysis: LCMS (ESI): 413 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.03-9.13(m, 1H) 8.61-8.78 (m, 1H) 8.01 (d, J=8.5 Hz, 1H) 7.71-7.82 (m, 1H) 7.63(d, J=8.5 Hz, 1H) 7.42 (d, J=8.8 Hz, 2H) 7.05 (d, J=8.8 Hz, 2H)4.79-4.85 (m, 1H) 4.57-4.64 (m, 1H) 4.44-4.49 (m, 1H) 2.71 (s, 3H)2.02-2.30 (m, 6H) 1.92 (d, J=7.8 Hz, 3H) 1.49-1.57 (m, 1H) 1.36-1.43 (m,2H) 0.70-0.80 (m, 2H).

Example 371.{endo-3-[4-(8-Methylquinolin-7-yl)-phenoxy]-8-aza-bicyclo[3.2.1]oct-8-yl}-(R)-tetrahydrofuran-2-yl-methanone,HCl

Analysis: LCMS (ESI): 443 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.06 (d,J=2.8 Hz, 1H) 8.65 (br. s., 1H) 7.99 (d, J=8.8 Hz, 1H) 7.70-7.80 (m, 1H)7.61 (d, J=8.3 Hz, 1H) 7.41 (d, J=8.5 Hz, 2H) 6.96-7.11 (m, 2H)4.77-4.85 (m, 1H) 4.55-4.61 (m, 1H) 4.48-4.52 (m, 1H) 4.41-4.45 (m, 1H)3.72-3.84 (m, 2H) 2.70 (s, 3H) 2.09-2.25 (m, 3H) 1.92-2.06 (m, 6H)1.74-1.90 (m, 3H).

Example 372.{(trans)-3-Fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone,HCl

Analysis: From cis-3-Fluoro-4-hydroxypiperidine-1-carboxylic acidt-butyl ester as a 1:1 mixture of diastereomers. LCMS (ESI): 435 (M+1);¹H NMR (400 MHz, DMSO-d₆, 95° C.) δ: 8.92-9.01 (m, 1H) 8.38-8.48 (m, 1H)7.86 (d, J=8.3 Hz, 1H) 7.57 (dd, J=8.3, 4.3 Hz, 1H) 7.48 (d, J=8.5 Hz,1H) 7.32-7.40 (m, 2H) 7.12-7.20 (m, 2H) 4.57-4.78 (m, 3H) 3.99-4.17 (m,1H) 3.73-3.85 (m, 4H) 3.37-3.50 (m, 1H) 2.68 (s, 3H) 1.97-2.17 (m, 3H)1.81-1.92 (m, 2H) 1.64-1.76 (m, 1H).

Example 373.1-{trans-3-Fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,HCl

Analysis: LCMS (ESI): 393 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.96 (dd,J=4.3, 1.8 Hz, 1H) 8.37 (dd, J=8.3, 1.8 Hz, 1H) 7.84 (d, J=8.3 Hz, 1H)7.54 (dd, J=8.3, 4.3 Hz, 1H) 7.46 (d, J=8.5 Hz, 1H) 7.36 (d, J=8.8 Hz,2H) 7.15 (d, J=8.8 Hz, 2H) 4.58-4.79 (m, 2H) 3.96-4.09 (m, 1H) 3.64-3.74(m, 2H) 3.54-3.62 (m, 1H) 3.40-3.49 (m, 1H) 2.67 (s, 3H) 2.32-2.41 (m,2H) 2.08-2.16 (m, 1H) 1.64-1.77 (m, 1H) 1.04 (t, J=7.4 Hz, 3H).

Example 374.Cyclopropyl-{trans-3-fluoro-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone,HCl

Analysis: LCMS (ESI): 405 (M+1); ¹H NMR (400 MHz, DMSO-d₆, 95° C.) δ:8.99 (dd, J=4.5, 1.8 Hz, 1H) 8.44 (dd, J=8.3, 1.8 Hz, 1H) 7.87 (d, J=8.5Hz, 1H) 7.59 (dd, J=8.2, 4.4 Hz, 1H) 7.50 (d, J=8.3 Hz, 1H) 7.37 (d,J=8.8 Hz, 2H) 7.17 (d, J=8.8 Hz, 2H) 4.70-4.79 (m, 2H) 4.61-4.66 (m, 1H)4.06-4.21 (m, 1H) 3.77-3.90 (m, 1H) 3.63-3.77 (m, 1H) 3.51-3.60 (m, 1H)2.69 (s, 3H) 2.08-2.19 (m, 1H) 1.92-2.03 (m, 1H) 1.67-1.79 (m, 1H)0.67-0.81 (m, 7H).

Example 375.1-{3-Methyl-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,TFA salt

From 4-Hydroxy-3-methyl-piperidine-1-carboxylic acid tert-butyl ester asa mixture of diastereomers. Analysis: LCMS (ESI): 389 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ: 8.99-9.06 (m, 1H) 8.46-8.58 (m, 1H) 7.88-7.98 (m, 1H)7.60-7.70 (m, 1H) 7.51-7.60 (m, 1H) 7.34-7.44 (m, 2H) 7.08-7.20 (m, 2H)4.15-4.70 (m, 1H) 2.91-3.90 (m, 4H) 2.69 (s, 3H) 2.31-2.42 (m, 2H)1.60-2.16 (m, 3H) 0.95-1.04 (m, 6H).

Example 376.Cyclopropyl-{3-methyl-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone,TFA salt

Analysis: LCMS (ESI): 401 (M+1); ¹H NMR (400 MHz, DMSO-d6) δ: 8.98-9.07(1H, m), 8.52 (1H, d, J=7.8 Hz), 7.93 (1H, d, J=8.3 Hz), 7.65 (1H, dd,J=8.2, 4.4 Hz), 7.55 (1H, d, J=8.5 Hz), 7.36-7.43 (2H, m), 7.10-7.18(2H, m), 4.62-4.74 (1H, m), 4.04-4.36 (1H, m), 3.74-3.90 (1H, m),3.48-3.71 (1H, m), 2.96-3.48 (1H, m), 2.69 (3H, s), 1.62-2.26 (4H, m),0.91-1.11 (3H, m), 0.67-0.82 (4H, m).

Example 377.{3-Methyl-4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone,TFA salt

Analysis: LCMS (ESI): 431 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.96-9.08(1H, m), 8.47-8.60 (1H, m), 7.86-7.98 (1H, m), 7.61-7.71 (1H, m),7.52-7.59 (1H, m), 7.35-7.43 (2H, m), 7.09-7.18 (2H, m), 4.59-4.84 (2H,m), 3.86-4.42 (1H, m), 2.90-3.84 (5H, m), 2.69 (3H, s), 1.61-2.22 (7H,m), 0.86-1.11 (3H, m).

Example 378.1-{4-[4-(6-Phenyl-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1. 4-[4-(6-Phenylpyridin-3-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester

To a schlenck flask was added4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol), 5-bromo-2-phenylpyridine (0.44 g,1.86 mmol), tetrakis(triphenylphosphine)palladium(0) (0.14 g, 0.12mmol), 1N sodium carbonate (3.72 mL, 3.72 mmol), followed by 1,4-dioxane(10 mL) and was degassed under an atmosphere of argon for 5 min and washeated at 100° C. overnight. The reaction was cooled, filtered through apad of celite, washed with 1N sodium carbonate, water, brine, dried oversodium sulfate, and concentrated. The product was purified via silicagel chromatography (10-30% EtOAc/hexanes) and concentrated was isolated(0.48 g, 90%). Analysis: LCMS m/z=431 (M+1).

Step 2. 2-Phenyl-5-[4-(piperidin-4-yloxy)-phenyl]-pyridine

To a solution of4-[4-(6-phenylpyridin-3-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester (0.48 g, 1.11 mmol) in DCM (10 mL) was added TFA (2 mL)dropwise and was stirred at rt for 1 h and concentrated. The reactionwas partitioned between DCM/1N Na₂CO₃, washed with water/brine, driedover sodium sulfate, and concentrated. Product was isolated as a beigesolid (0.37 g, 100%). LCMS m/z=331 (M+1).

Step 3

To 2-phenyl-5-[4-(piperidin-4-yloxy)-phenyl]-pyridine (94 mg, 0.28 mmol)in DCM (5 mL) was added TEA (1 mL, 7 mmol), followed by propanoylchloride (40 uL, 0.5 mmol) dropwise and the reaction was stirred at rtfor 1 h. The reaction was diluted with DCM, washed with 1N Na₂CO₃,water, and brine, dried over Na₂SO₄, and concentrated. The product waspurified using the Gilson (0.1% TFA in water/0.1% TFA in acetonitrilegradient) and placed on the lyophilizer overnight.1-{4-[4-(6-Phenyl-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-oneTFA salt was isolated (0.07 g, 49%). Analysis: LCMS m/z=387 (M+1). ¹HNMR (DMSO-d6) δ: 8.97 (m, 1H), 8.14 (m, 3H), 8.05 (d, 1H, J=8.3 Hz),7.75 (d, 2H, J=8.7 Hz), 7.53 (m, 2H), 7.45 (m, 1H), 7.14 (d, 2H, J=8.8Hz), 4.70 (m, 1H), 3.87 (m, 1H), 3.69 (m, 1H), 3.26 (m, 2H), 2.33 (m,2H), 1.97 (m, 2H), 1.54 (m, 2H), 0.99 (t, 3H, J=7.4 Hz).

Example 379.2-Methyl-1-{4-[4-(6-phenylpyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

To 2-phenyl-5-[4-(piperidin-4-yloxy)-phenyl]-pyridine (94 mg, 0.28 mmol)in DCM (5 mL) was added triethylamine (1 mL, 7 mmol), followed byisobutyryl chloride (50 uL, 0.5 mmol) drop wise and the reaction wasstirred at rt for 1 h and concentrated. The reaction was partitionedbetween DCM/1N sodium carbonate, washed with water/brine, dried oversodium sulfate, and concentrated. The product was purified via silicagel chromatography (8% methanol/DCM) and concentrated.2-Methyl-1-{4-[4-(6-phenyl-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-onewas isolated as a solid (0.07 g, 57%). Analysis: LCMS m/z=401 (M+1). ¹HNMR (DMSO-d₆) δ: 8.96 (m, 1H), 8.14 (m, 3H), 8.03 (d, 1H, J=8.2 Hz),7.72 (m, 2H), 7.51 (m, 2H), 7.44 (m, 1H), 7.14 (d, 2H, J=8.8 Hz), 4.71(m, 1H), 3.88 (m, 1H), 3.77 (m, 1H), 3.40 (m, 1H), 3.26 (m, 1H), 2.90(m, 1H), 1.99 (m, 2H), 1.53 (m, 2H), 1.01 (d, 6H, J=6.7 Hz).

The following examples were synthesized using the procedure for Examples378 and 379.

Example 380.Cyclopropyl-{4-[4-(6-phenyl-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=399 (M+1). ¹H NMR (DMSO-d6) δ: 8.96 (m, 1H), 8.14 (m,3H), 8.03 (d, 1H, J=8.2 Hz), 7.72 (m, 2H), 7.51 (m, 2H), 7.44 (m, 1H),7.14 (d, 2H, J=8.8 Hz), 4.72 (m, 1H), 4.07 (m, 1H), 3.98 (m, 1H), 3.55(m, 1H), 3.29 (m, 1H), 2.00 (m, 3H), 1.54-1.64 (br m, 2H), 0.71 (m, 4H).

Example 381.Cyclobutyl-{4-[4-(6-phenyl-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS m/z=413 (M+1). ¹H NMR (DMSO-d6) δ: 8.96 (m, 1H), 8.14 (m,3H), 8.03 (d, 1H, J=8.2 Hz), 7.72 (m, 2H), 7.51 (m, 2H), 7.44 (m, 1H),7.14 (d, 2H, J=8.8 Hz), 4.69 (m, 1H), 3.85 (m, 1H), 3.56 (m, 1H), 3.36(m, 1H), 3.25 (m, 2H), 2.09 (m, 4H), 1.92 (m, 3H), 1.74 (m, 1H), 1.55(m, 2H).

Example 382.1-{4-[4-(5-Phenylpyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1. 4-[4-(5-Phenyl-pyridin-3-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester

The compound was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and 3-bromo-5-phenylpyridine (0.44g, 1.86 mmol) in an analogous manner to Example 378. Product wasisolated as a solid (0.51 g, 96%). Analysis: LCMS m/z=431 (M+1).

Step 2. 3-Phenyl-5-[4-(piperidin-4-yloxy)-phenyl]-pyridine

The compound was prepared from4-[4-(5-phenyl-pyridin-3-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester (0.48 mg, 1.11 mmol) and TFA (2 mL) in an analogousmanner to Example 378. The product was isolated as a solid (0.37 g,100%). Analysis: LCMS m/z=331 (M+1).

Step 3.1-{4-[4-(5-Phenylpyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

The compound was prepared from3-phenyl-5-[4-(piperidin-4-yloxy)-phenyl]-pyridine (95 mg, 0.29 mmol)and propanoyl chloride (40 uL, 0.5 mmol) in an analogous manner toExample 378 to give a solid (0.06 g, 54%). Analysis: LCMS m/z=387 (M+1).¹H NMR (DMSO-d6) δ: 8.82 (m, 2H), 8.25 (m, 1H), 7.83 (m, 2H), 7.77 (m,2H), 7.53 (m, 2H), 7.45 (m, 1H), 7.12 (m, 2H), 4.71 (m, 1H), 3.86 (m,1H), 3.70 (m, 1H), 3.27 (m, 2H), 2.33 (m, 2H), 1.97 (m, 2H), 1.61 (m,2H), 0.99 (t, 3H, J=7.4 Hz).

Example 383.2-Methyl-1-{4-[4-(5-phenylpyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS m/z=401 (M+1). ¹H NMR (DMSO-d6) δ: 8.82 (m, 2H), 8.25 (m,1H), 7.83 (m, 2H), 7.77 (m, 2H), 7.53 (m, 2H), 7.45 (m, 1H), 7.12 (m,2H), 4.72 (m, 1H), 3.87 (m, 1H), 3.76 (m, 1H), 3.41 (m, 1H), 3.29 (m,1H), 2.90 (m, 1H), 1.99 (m, 2H), 1.54 (m, 2H), 1.01 (d, 6H, J=6.6 Hz).

Example 384.Cyclopropyl-{4-[4-(5-phenyl-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone,TFA salt

Analysis: LCMS m/z=399 (M+1). ¹H NMR (DMSO-d6) δ: 8.94 (m, 2H), 8.52 (m,1H), 7.90 (m, 4H), 7.56 (m, 2H), 7.49 (m, 1H), 7.18 (m, 2H), 4.76 (m,1H), 3.99 (m, 1H), 3.89 (m, 1H), 3.56 (m, 1H), 3.29 (m, 1H), 2.00 (m,3H), 1.55 (br m, 2H), 0.71 (m, 4H).

Example 385.Cyclobutyl-{4-[4-(5-phenylpyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone,TFA salt

This example was synthesized from3-phenyl-5-[4-(piperidin-4-yloxy)-phenyl]-pyridine (95 mg, 0.29 mmol)and cyclobutanecarbonyl chloride (60 uL, 0.5 mmol) to give a solid (0.08g, 50%). Analysis: LCMS m/z=413 (M+1). ¹H NMR (DMSO-d6) δ: 8.94 (m, 2H),8.52 (m, 1H), 7.90 (m, 4H), 7.56 (m, 2H), 7.49 (m, 1H), 7.18 (m, 2H),4.72 (m, 1H), 3.84 (m, 1H), 3.56 (m, 1H), 3.36 (m, 1H), 3.26 (m, 2H),2.09 (br m, 4H), 1.93 (m, 3H), 1.74 (m, 1H), 1.56 (m, 2H).

Example 386.1-{4-[4-(6-Morpholin-4-yl-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1.4-[4-(6-Morpholin-4-yl-pyridin-3-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester

The compound was prepared from 4-(4-iodophenoxy)-piperidine-1-carboxylicacid tert-butyl ester (0.5 g, 1.24 mmol) and4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-yl]-morpholine(0.54 g, 1.86 mmol) as described previously. Product isolated as a solid(0.44 g, 81%). Analysis: LCMS m/z=440 (M+1).

Step 2. 4-{5-[4-(Piperidin-4-yloxy)-phenyl]-pyridin-2-yl}-morpholine

The compound was prepared from4-[4-(6-morpholin-4-yl-pyridin-3-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.44 mg, 1.01 mmol) and TFA (2 mL). The productisolated as a solid (0.34 g, 100%). Analysis: LCMS m/z=340 (M+1).

Step 3.1-{4-[4-(6-Morpholin-4-yl-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

The compound was prepared from4-{5-[4-(piperidin-4-yloxy)-phenyl]-pyridin-2-yl}-morpholine (95 mg,0.28 mmol) and propanoyl chloride (40 uL, 0.5 mmol). The product wasisolated as a solid (0.04 g, 36%). Analysis: LC/MS 396 (M+H). ¹H NMR(DMSO-d6) δ: 8.41 (d, 1H, J=2.3 Hz), 7.81 (m, 1H), 7.54 (m, 2H), 7.03(m, 2H), 6.90 (d, 1H, J=8.8 Hz), 4.63 (m, 1H), 3.84 (m, 1H), 3.71 (m,5H), 3.46 (m, 4H), 3.33 (m, 1H), 3.24 (m, 1H), 2.32 (m, 2H), 1.94 (m,2H), 1.51 (m, 2H), 0.99 (t, 3H, J=7.4 Hz).

Example 387.Cyclopropyl-{4-[4-(6-morpholin-4-yl-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

This example was synthesized from4-{5-[4-(piperidin-4-yloxy)-phenyl]-pyridin-2-yl}-morpholine (95 mg,0.28 mmol) and cyclopropanecarbonyl chloride (40 μL, 0.5 mmol). Theproduct was isolated as a solid (0.07 g, 61%). Analysis: LCMS m/z=408(M+1). ¹H NMR (DMSO-d6) δ: 8.41 (d, 1H, J=2.3 Hz), 7.81 (m, 1H), 7.54(m, 2H), 7.03 (m, 2H), 6.90 (d, 1H, J=8.8 Hz), 4.66 (m, 1H), 3.96 (m,1H), 3.87 (m, 1H), 3.71 (m, 4H), 3.53 (m, 1H), 3.46 (m, 4H), 3.29 (m,1H), 1.99 (m, 2H), 1.97 (m, 1H), 1.63 (m, 1H), 1.52 (m, 1H), 0.71 (m,4H).

Example 388.Cyclobutyl-{4-[4-(6-morpholin-4-yl-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Synthesized from4-{5-[4-(piperidin-4-yloxy)-phenyl]-pyridin-2-yl}-morpholine (95 mg,0.28 mmol) and cyclobutanecarbonyl chloride (50 uL, 0.5 mmol). Productisolated as a solid (0.06 g, 51%). Analysis: LCMS m/z=422 (M+1). ¹H NMR(DMSO-d6) δ: 8.41 (d, 1H, J=2.3 Hz), 7.81 (m, 1H), 7.54 (m, 2H), 7.03(m, 2H), 6.90 (d, 1H, J=8.8 Hz), 4.62 (m, 1H), 3.86 (m, 1H), 3.71 (m,4H), 3.58 (m, 1H), 3.46 (m, 4H), 3.33 (m, 1H), 3.23 (m, 2H), 2.06-2.19(br m, 4H), 1.90 (m, 3H), 1.74 (m, 1H), 1.49 (m, 2H).

Example 389.1-{4-[4-(6-Phenoxy-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1. 4-[4-(6-Phenoxy-pyridin-3-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester

The compound was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and 5-bromo-2-phenoxy-pyridine(0.47 g, 1.86 mmol) in an analogous manner to Example 378. Productisolated as a solid (0.44 g, 80%). Analysis: LCMS m/z=447 (M+1).

Step 2. 2-Phenoxy-5-[4-(piperidin-4-yloxy)-phenyl]-pyridine

The compound was prepared from4-[4-(6-phenoxy-pyridin-3-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester (0.44 g, 0.99 mmol) and TFA (2 mL). The product wasisolated as a solid (0.32 g, 95%). Analysis: LCMS m/z=347 (M+1).

Step 3.1-{4-[4-(6-Phenoxypyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

The compound was prepared from2-phenoxy-5-[4-(piperidin-4-yloxy)-phenyl]-pyridine (95 mg, 0.27 mmol)and propanoyl chloride (40 uL, 0.5 mmol) to give a solid (0.07 g, 60%).Analysis: LCMS m/z=403 (M+1). ¹H NMR (DMSO-d6) δ: 8.40 (d, 1H, J=2.2Hz), 8.08 (m, 1H), 7.58 (m, 2H), 7.43 (m, 2H), 7.22 (m, 1H), 7.16 (m,2H), 7.09 (m, 3H), 4.66 (m, 1H), 3.89 (m, 1H), 3.71 (m, 1H), 3.35 (m,1H), 3.24 (m, 1H), 2.32 (m, 2H), 1.95 (m, 2H), 1.49-1.62 (br m, 2H),0.99 (t, 3H, J=7.4 Hz).

Example 390.Cyclopropyl-{4-[4-(6-phenoxy-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

This example was synthesized from2-phenoxy-5-[4-(piperidin-4-yloxy)-phenyl]-pyridine (95 mg, 0.27 mmol)and cyclopropanecarbonyl chloride (40 uL, 0.5 mmol) to give a solid(0.08 g, 70%). Analysis: LCMS m/z=415 (M+1). ¹H NMR (DMSO-d6) δ: 8.40(d, 1H, J=2.2 Hz), 8.08 (m, 1H), 7.58 (m, 2H), 7.43 (m, 2H), 7.22 (m,1H), 7.16 (m, 2H), 7.09 (m, 3H), 4.70 (m, 1H), 3.97 (m, 1H), 3.87 (m,1H), 3.54 (m, 1H), 3.26 (m, 1H), 1.91-2.02 (br m, 3H), 1.62 (m, 1H),1.52 (m, 1H), 0.71 (m, 4H).

Example 391.Cyclobutyl-{4-[4-(6-phenoxy-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

This example was synthesized from2-phenoxy-5-[4-(piperidin-4-yloxy)-phenyl]-pyridine (95 mg, 0.27 mmol)and cyclobutanecarbonyl chloride (50 uL, 0.5 mmol) to give a solid (0.09g, 72%). Analysis: LCMS m/z=429 (M+1). ¹H NMR (DMSO-d6) δ: 8.40 (d, 1H,J=2.2 Hz), 8.08 (m, 1H), 7.58 (m, 2H), 7.43 (m, 2H), 7.22 (m, 1H), 7.16(m, 2H), 7.09 (m, 3H), 4.65 (m, 1H), 3.87 (m, 1H), 3.55 (m, 1H), 3.35(m, 1H), 3.23 (m, 2H), 2.06-2.19 (br m, 4H), 1.90 (br m, 3H), 1.74 (m,1H), 1.53 (m, 2H).

Example 392.1-{4-[4-(6-Phenylaminopyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,TFA salt

Step 1.4-[4-(6-Phenylaminopyridin-3-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester

The compound was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and(5-bromo-pyridin-2-yl)-phenyl-amine (0.46 g, 1.86 mmol) to give a solid.Analysis: LCMS m/z=446 (M+1).

Step 2. Phenyl-{5-[4-(piperidin-4-yloxy)-phenyl]-pyridin-2-yl}-amine

The compound was prepared from4-[4-(6-phenylamino-pyridin-3-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester and trifluoroacetic acid (2 mL). Product isolated as asolid. Analysis: LCMS m/z=346 (M+1).

Step 3.1-{4-[4-(6-Phenylaminopyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,TFA salt

The compound was prepared fromphenyl-{5-[4-(piperidin-4-yloxy)-phenyl]-pyridin-2-yl}-amine (95 mg,0.27 mmol) and propanoyl chloride (40 uL, 0.5 mmol). Product isolated asa solid (0.03 g, 21%). Analysis: LCMS m/z 402 (M+1). ¹H NMR (DMSO-d6) δ:9.55 (br s, 1H), 8.36 (d, 1H, J=2.2 Hz), 7.99 (m, 1H), 7.59 (m, 4H),7.34 (m, 2H), 7.08 (m, 4H), 4.66 (m, 1H), 3.85 (m, 1H), 3.71 (m, 1H),3.25 (m, 2H), 2.33 (m, 2H), 1.95 (m, 2H), 1.47-1.64 (br m, 2H), 0.99 (t,3H, J=7.3 Hz).

Example 393.Cyclopropyl-{4-[4-(6-phenylaminopyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone,TFA salt

Prepared fromphenyl-{5-[4-(piperidin-4-yloxy)-phenyl]-pyridin-2-yl}-amine (95 mg,0.27 mmol) and cyclopropanecarbonyl chloride (40 uL, 0.5 mmol) to give asolid (0.08 g, 55%). Analysis: LCMS m/z=414 (M+1). ¹H NMR (DMSO-d6) δ:9.55 (br s, 1H), 8.36 (d, 1H, J=2.2 Hz), 7.99 (m, 1H), 7.59 (m, 4H),7.34 (m, 2H), 7.08 (m, 4H), 4.68 (m, 1H), 3.88-3.97 (br m, 2H), 3.54 (m,1H), 3.27 (m, 1H), 1.91-2.02 (br m, 3H), 1.49-1.79 (br m, 2H), 1.01 (m,4H).

Example 394.Cyclobutyl-{4-[4-(6-phenylaminopyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone,TFA salt

This example was synthesized fromphenyl-{5-[4-(piperidin-4-yloxy)-phenyl]-pyridin-2-yl}-amine (95 mg,0.27 mmol) and cyclobutanecarbonyl chloride (50 uL, 0.5 mmol) to give asolid (0.05 g, 34%). LCMS m/z=428 (M+1). ¹H NMR (DMSO) δ: 9.55 (br s,1H), 8.36 (d, 1H, J=2.2 Hz), 7.99 (m, 1H), 7.59 (m, 4H), 7.34 (m, 2H),7.08 (m, 4H), 4.64 (m, 1H), 3.84 (m, 1H), 3.58 (m, 1H), 3.35 (m, 1H),3.21 (m, 2H), 2.05-2.19 (br m, 4H), 1.85-1.94 (br m, 3H), 1.74 (m, 1H),1.53 (m, 2H).

Example 395.1-[4-(2′-Fluoro-3′-pyridin-2-yl-biphenyl-4-yloxy)-piperidin-1-yl]-propan-1-one

Step 1

To a schlenck flask was added (3-bromo-2-fluorophenyl)boronic acid (0.5g, 2.28 mmol), 2-bromopyridine (0.32 mL, 3.43 mmol),tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.23 mmol), 1N Na₂CO₃(6.9 mL, 6.86 mmol), followed by 1,4-dioxane (10 mL) and was degassedunder an atmosphere of argon for 5 min and was heated at 100° C. for 1h. The reaction was cooled, filtered through a pad of celite, washedwith 1N Na₂CO₃, water and brine, dried over sodium sulfate, andconcentrated. The product was purified via silica gel chromatography(10% ethyl acetate/hexanes) and concentrated to give2-(3-bromo-2-fluoro-phenyl)-pyridine (0.54 g, 94%). Analysis: LCMSm/z=253 (M+1).

Step 2

4-(2′-Fluoro-3′-pyridin-2-yl-biphenyl-4-yloxy)-piperidine-1-carboxylicacid t-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (0.5 g, 1.24 mmol) and2-(3-bromo-2-fluoro-phenyl)-pyridine (0.54 g, 2.15 mmol) Analysis: LCMSm/z=449 (M+1).

Step 3

2-[2-Fluoro-4′-(piperidin-4-yloxy)-biphenyl-3-yl]-pyridine was preparedfrom4-(2′-fluoro-3′-pyridin-2-yl-biphenyl-4-yloxy)-piperidine-1-carboxylicacid tert-butyl ester and trifluoroacetic acid (2 mL) to give a solid.Analysis: LCMS m/z=349 (M+1).

Step 4

1-[4-(2′-Fluoro-3′-pyridin-2-yl-biphenyl-4-yloxy)-piperidin-1-yl]-propan-1-onewas prepared from2-[2-fluoro-4′-(piperidin-4-yloxy)-biphenyl-3-yl]-pyridine (73 mg, 0.21mmol) and propanoyl chloride (30 uL, 0.4 mmol). Product isolated as asolid (0.03 g, 35%). Analysis: LCMS m/z=405 (M+H). ¹H NMR (DMSO-d6) δ:8.73 (m, 1H), 7.93 (m, 1H), 7.81 (m, 2H), 7.54 (m, 3H), 7.38 (m, 2H),7.11 (d, 2H, J=8.7 Hz), 4.69 (m, 1H), 3.87 (m, 1H), 3.69 (m, 1H), 3.34(m, 1H), 3.25 (m, 1H), 2.35 (m, 2H), 1.97 (m, 2H), 1.54 (br m, 2H), 0.99(t, 3H, J=7.3 Hz).

Example 396.Cyclopropyl-[4-(2′-fluoro-3′-pyridin-2-yl-biphenyl-4-yloxy)-piperidin-1-yl]-methanone

To 2-[2-fluoro-4′-(piperidin-4-yloxy)-biphenyl-3-yl]-pyridine (73 mg,0.21 mmol) in DCM (4 mL) was added triethylamine (0.7 mL, 5 mmol),followed by cyclopropanecarbonyl chloride (30 uL, 0.4 mmol) dropwise andthe reaction was stirred at rt for 1 h and concentrated. The reactionwas partitioned between DCM and 1N Na₂CO₃, washed with water/brine,dried over sodium sulfate, and concentrated. The product was purifiedusing the Gilson (0.1% TFA in water/0. 1% TFA in acetonitrile gradient),diluted clean fractions with DCM, washed with 1N sodium carbonate/brine,dried over sodium sulfate, and concentrated to give a solid (0.03 g,25%). Analysis: LCMS m/z=417 (M+1). ¹H NMR (DMSO-d6) δ: 8.73 (m, 1H),7.93 (m, 1H), 7.81 (m, 2H), 7.54 (m, 3H), 7.38 (m, 2H), 7.11 (d, 2H,J=8.7 Hz), 4.71 (m, 1H), 3.99 (m, 1H), 3.89 (m, 1H), 3.55 (m, 1H), 3.29(m, 1H), 2.00 (br m, 3H), 1.54-1.64 (br m, 2H), 0.71 (m, 4H).

Example 397.1-{4-[4-(5-Phenoxypyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,TFA

Step 1

4-[4-(5-Phenoxypyridin-3-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from4-(4-iodo-phenoxy)-piperidine-1-carboxylic acid t-butyl ester (0.5 g,1.24 mmol) and (5-phenoxy-3-pyridyl)boronic acid (0.4 g, 1.86 mmol).LCMS m/z=447 (M+1).

Step 2

3-Phenoxy-5-[4-(piperidin-4-yloxy)-phenyl]-pyridine was prepared from4-[4-(5-phenoxypyridin-3-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester and TFA (2 mL). Analysis: LCMS m/z=347 (M+1).

Step 3.1-{4-[4-(5-Phenoxypyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

TFA salt was prepared from3-phenoxy-5-[4-(piperidin-4-yloxy)-phenyl]-pyridine (90 mg, 0.2 mmol)and propanoyl chloride (40 uL, 0.4 mmol) to give a solid (0.09 g, 70%).Analysis: LCMS m/z=403 (M+1). ¹H NMR (DMSO-d6) δ: 8.72 (br s, 1H), 8.34(br s, 1H), 7.77 (m, 1H), 7.69 (m, 2H), 7.46 (m, 2H), 7.23 (m, 1H), 7.11(m, 4H), 4.69 (m, 1H), 3.85 (m, 1H), 3.71 (m, 1H), 3.36 (m, 2H), 2.32(m, 2H), 1.95 (m, 2H), 1.48-1.62 (br m, 2H), 0.99 (t, 3H, J=7.4 Hz).

Example 398.Cyclobutyl-[4-(2′-fluoro-3′-pyridin-2-yl-biphenyl-4-yloxy)-piperidin-1-yl]-methanone,HCl

To 2-[2-fluoro-4′-(piperidin-4-yloxy)-biphenyl-3-yl]-pyridine (73 mg,0.21 mmol) in DCM (4 mL) was added TEA (0.7 mL, 5 mmol), followed bycyclobutanecarbonyl chloride (40 uL, 0.4 mmol) dropwise and the reactionwas stirred at rt for 1 h. The reaction was partitioned between DCM/1NNa₂CO₃, washed with water/brine, dried over Na₂SO₄, and concentrated.The product was purified using Gilson (0.1% TFA in water/0.1% TFA inacetonitrile gradient), clean fractions diluted with DCM, washed with 1NNa₂CO₃/water/brine, dried over Na₂SO₄, and concentrated. The compoundwas dissolved in DCM, 2M of HCl in diethyl ether (105 uL, 0.21 mmol) wasadded and concentrated, then dried under vacuum at 65° C. overnight togive a solid (0.03 g, 31%). Analysis: LCMS m/z=431 (M+1). ¹H NMR(DMSO-d6) δ: 8.79 (m, 1H), 8.07 (m, 1H), 7.92 (m, 1H), 7.80 (m, 1H),7.57 (m, 4H), 7.41 (m, 1H), 7.11 (m, 2H), 4.68 (m, 1H), 3.89 (m, 1H),3.56 (m, 1H), 3.36 (m, 1H), 3.24 (m, 2H), 2.05-2.22 (br m, 4H), 1.92 (brm, 3H), 1.74 (m, 1H), 1.55 (m, 2H).

Example 399.Cyclopropyl-{4-[4-(5-phenoxy-pyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone,HCl

The compound was prepared from3-phenoxy-5-[4-(piperidin-4-yloxy)-phenyl]-pyridine (90 mg, 0.2 mmol)and cyclopropanecarbonyl chloride (40 uL, 0.4 mmol). Product isolated asa solid (0.05 g, 40%). Analysis: LCMS m/z=415 (M+1). ¹H NMR (DMSO-d6) δ:8.73 (m, 1H), 8.34 (d, 1H, J=2.2 Hz), 7.81 (m, 1H), 7.70 (m, 2H), 7.45(m, 2H), 7.22 (m, 1H), 7.16 (m, 4H), 4.72 (m, 1H), 3.97 (m, 1H), 3.87(m, 1H), 3.54 (m, 1H), 3.26 (m, 1H), 1.90-2.02 (br m, 3H), 1.62 (br m,2H), 0.70 (m, 4H).

Example 400.Cyclobutyl-{4-[4-(5-phenoxypyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone,HCl

This example was prepared from3-phenoxy-5-[4-(piperidin-4-yloxy)-phenyl]-pyridine (90 mg, 0.2 mmol)and cyclobutanecarbonyl chloride (50 uL, 0.4 mmol) to give a solid (0.04g, 30%). Analysis: LCMS m/z=429 (M+1). ¹H NMR (DMSO-d6) δ: 8.74 (d, 1H,J=1.7 Hz), 8.35 (d, 1H, J=2.5H), 7.83 (m, 1H), 7.70 (m, 2H), 7.47 (m,2H), 7.24 (m, 1H), 7.16 (m, 2H), 7.09 (m, 2H), 4.68 (m, 1H), 3.85 (m,1H), 3.58 (m, 1H), 3.35 (m, 1H), 3.23 (m, 2H), 2.04-2.21 (br m, 4H),1.92 (br m, 3H), 1.74 (m, 1H), 1.51 (m, 2H).

Example 401.1-{4-[4-(5-Phenylaminopyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,TFA salt

Step 1

4-[4-(5-Bromopyridin-3-yl)-phenoxy]-piperidine-1-carboxylic acid t-butylester was prepared from 4-(4-iodophenoxy)-piperidine-1-carboxylic acidt-butyl ester (0.5 g, 1.24 mmol) and (5-bromo-3-pyridyl)boronic acid(0.38 g, 1.86 mmol) in an analogous manner to Example 378. Productisolated as a solid (0.14 g, 25%). Analysis: LCMS m/z=434 (M+1).

Step 2

To an oven dried schlenck flask under an atmosphere of argon was chargedwith 4-[4-(5-bromo-pyridin-3-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester (0.14 g, 0.31 mmol), aniline (0.04 mL, 0.47 mmol),tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.02 mmol),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (36 mg, 0.06 mmol),sodium t-butoxide (90 mg, 0.94 mmol), followed by 1,4-dioxane (5 mL) andthe reaction was degassed 3-times under an atmosphere of argon and washeated at 100° C. for 2 h. The mixture was cooled, filtered through apad of celite, washed with DCM, and concentrated. The product waspurified via silica gel chromatography (10-30% EtOAc/hexanes) andconcentrated.4-[4-(5-Phenylamino-pyridin-3-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was isolated (0.12 g, 88%). Analysis: LCMS m/z=446 (M+1).

Step 3

Phenyl-{5-[4-(piperidin-4-yloxy)-phenyl]-pyridin-3-yl}-amine wasprepared from4-[4-(5-phenylamino-pyridin-3-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester (0.12 g, 0.27 mmol) and TFA (1 mL) in an analogous mannerto Example 599b. Product isolated as a solid (0.07 g, 75%). Analysis:LCMS m/z=346 (M+1).

Step 4

The product was prepared fromphenyl-{5-[4-(piperidin-4-yloxy)-phenyl]-pyridin-3-yl}-amine (71 mg,0.20 mmol) and propanoyl chloride (21 uL, 0.25 mmol) in an analogousmanner to Example 599c. Product isolated as a solid (0.04 g, 33%).Analysis: LCMS m/z=402 (M+1). ¹H NMR (DMSO-d6) δ: 9.00 (s, 1H), 8.45 (d,1H, J=1 Hz), 8.32 (d, 1H, J=2.1 Hz), 7.95 (m, 1H), 7.66 (m, 2H), 7.39(m, 2H), 7.27 (m, 2H), 7.15 (m, 2H), 7.05 (m, 1H), 4.71 (m, 1H), 3.87(m, 1H), 3.72 (m, 1H), 3.36 (m, 1H), 3.25 (m, 1H), 2.33 (m, 2H),1.91-1.97 (br m, 2H), 1.50-1.63 (br m, 2H), 0.99 (t, 3H, J=7.4 Hz).

Example 402.1-{4-[4-(2-Phenylpyridin-4-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,TFA

Step 1

4-[4-(2-Bromopyridin-4-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester was prepared from4-(4-iodo-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.5 g,1.24 mmol) and (2-bromo-4-pyridyl)boronic acid (0.38 g, 1.86 mmol)Product isolated as a solid (0.19 g, 36%). Analysis: LCMS m/z 434 (M+1).

Step 2

4-[4-(2-Phenylpyridin-4-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester was prepared from4-[4-(2-bromopyridin-4-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester (0.19 g, 0.44 mmol) and phenylboronic acid (81 mg, 0.67mmol). Product isolated as a solid. Analysis: LCMS m/z=431 (M+1).

Step 3

2-Phenyl-4-[4-(piperidin-4-yloxy)-phenyl]-pyridine was prepared from4-[4-(2-phenylpyridin-4-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester and TFA (1 mL). Product isolated as a solid. Analysis:LCMS m/z=331 (M+1).

Step 4

The title product was prepared from2-phenyl-4-[4-(piperidin-4-yloxy)-phenyl]-pyridine (56 mg, 0.17 mmol)and propanoyl chloride (29 uL, 0.34 mmol). Product isolated as a solid(0.05 g, 59%). Analysis: LCMS m/z 387 (M+1). ¹H NMR (DMSO-d6) δ: 8.74(d, 1H, J=5.6 Hz), 8.33 (s, 1H), 8.15 (m, 2H), 7.98 (m, 2H), 7.87 (d,1H, J=4.4 Hz), 7.56 (m, 3H), 7.19 (m, 2H), 4.77 (m, 1H), 3.87 (m, 1H),3.72 (m, 1H), 3.24-3.38 (m, 2H), 2.33 (m, 2H), 1.98 (m, 2H), 1.53-1.65(br m, 2H), 0.99 (t, 3H, J=7.4 Hz).

Example 403.Cyclopropyl-{4-[4-(2-phenylpyridin-4-yl)-phenoxy]-piperidin-1-yl}-methanone,TFA salt

This example was prepared from2-phenyl-4-[4-(piperidin-4-yloxy)-phenyl]-pyridine (56 mg, 0.17 mmol)and cyclopropanecarbonyl chloride (31 uL, 0.34 mmol). Product isolatedas a solid (0.35 g, 40%). Analysis: LCMS m/z=399 (M+1). ¹H NMR (DMSO-d6)δ: 8.74 (d, 1H, J=5.6 Hz), 8.33 (s, 1H), 8.15 (m, 2H), 7.98 (m, 2H),7.87 (d, 1H, J=4.4 Hz), 7.56 (m, 3H), 7.19 (m, 2H), 4.79 (m, 1H),3.89-3.98 (br m, 2H), 3.57 (m, 1H), 3.29 (m, 1H), 2.00 (br m, 3H),1.50-1.79 (br m, 2H), 0.71 (m, 4H).

Example 404.1-{4-[4-(2-Phenylaminopyridin-4-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1

4-[4-(2-Chloropyridin-4-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from4-(4-iodophenoxy)-piperidine-1-carboxylic acid t-butyl ester (0.5 g,1.24 mmol) and 2-chloropyridine-4-boronic acid (0.29 g, 1.86 mmol).Product isolated as a solid (0.24 g, 49%). Analysis: LCMS m/z 389 (M+1).

Step 2

4-[4-(2-Phenylaminopyridin-4-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester was prepared from4-[4-(2-chloro-pyridin-4-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester (0.24 g, 0.61 mmol) and aniline (0.08 mL, 0.91 mmol) inan analogous manner to Example 402, Step 2. Product isolated as a solid(0.19 g, 69%). Analysis: LCMS m/z 446 (M+1).

Step 3

Phenyl-{4-[4-(piperidin-4-yloxy)-phenyl]-pyridin-2-yl}-amine wasprepared from4-[4-(2-phenylaminopyridin-4-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester (0.19 g, 0.42 mmol) and trifluoroacetic acid (1 mL).Product isolated as a solid (0.14 g, 100%). Analysis: LCMS m/z 346(M+1).

Step 4

The title product was prepared fromphenyl-{4-[4-(piperidin-4-yloxy)-phenyl]-pyridin-2-yl}-amine (73 mg,0.21 mmol) and propanoyl chloride (28 uL, 0.32 mmol) in an analogousmanner to Example 396. Product isolated as a solid (0.03 g, 35%).Analysis: LCMS m/z=402 (M+1). ¹H NMR (DMSO-d6) δ: 9.04 (s, 1H), 8.17 (d,1H, J=5.4 Hz), 7.70 (d, 2H, J=7.6 Hz), 7.65 (d, 2H, J=8.8 Hz), 7.26 (m,2H), 7.13 (d, 2H, J=8.8 Hz), 7.02 (m, 2H), 6.88 (m, 1H), 4.69 (m, 1H),3.88 (m, 1H), 3.70 (m, 1H), 3.37 (m, 1H), 3.25 (m, 1H), 2.33 (m, 2H),1.96 (br m, 2H), 1.50-1.63 (br m, 2H), 0.99 (t, 3H, J=7.4 Hz).

Example 405.Cyclopropyl-{4-[4-(2-phenylaminopyridin-4-yl)-phenoxy]-piperidin-1-yl}-methanone

This example was prepared fromphenyl-{4-[4-(piperidin-4-yloxy)-phenyl]-pyridin-2-yl}-amine (73 mg,0.21 mmol) and cyclopropanecarbonyl chloride (29 uL, 0.32 mmol) in ananalogous manner to Example 396. Product isolated as a solid (0.04 g,40%). Analysis: LCMS m/z=414 (M+1). ¹H NMR (DMSO-d6) δ: 9.04 (s, 1H),8.17 (d, 1H, J=5.4 Hz), 7.70 (d, 2H, J=7.6 Hz), 7.65 (d, 2H, J=8.8 Hz),7.26 (m, 2H), 7.13 (d, 2H, J=8.8 Hz), 7.02 (m, 2H), 6.88 (m, 1H), 4.72(m, 1H), 3.98 (m, 1H), 3.89 (m, 1H), 3.55 (m, 1H), 3.29 (m, 1H),1.94-2.03 (br m, 3H), 1.54-1.64 (br m, 2H), 0.71 (m, 4H).

Example 406.1-[4-(2′-Methyl-3′-pyridin-2-yl-biphenyl-4-yloxy)-piperidin-1-yl]-propan-1-one;TFA salt

Step 1

2-(3-Bromo-2-methylphenyl)-pyridine was prepared from3-bromo-2-methyl-phenylboronic acid (0.5 g, 2.33 mmol) and2-bromopyridine (0.33 mL, 3.49 mmol) in an analogous manner to Example378. Product isolated as a solid (0.5 g, 87%). Analysis: LCMS m/z 249(M+1).

Step 2

4-(2′-Methyl-3′-pyridin-2-yl-biphenyl-4-yloxy)-piperidine-1-carboxylicacid tert-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (0.5 g, 1.24 mmol) and2-(3-bromo-2-methyl-phenyl)-pyridine (0.46 g, 1.86 mmol) in an analogousmanner to Example 378. Product isolated as a solid (0.5 g, 89%).Analysis: LCMS m/z 445 (M+1).

Step 3

2-[2-Methyl-4′-(piperidin-4-yloxy)-biphenyl-3-yl]-pyridine was preparedfrom4-(2′-methyl-3′-pyridin-2-yl-biphenyl-4-yloxy)-piperidine-1-carboxylicacid tert-butyl ester (0.5 g, 1.11 mmol) and TFA (2 mL) in an analogousmanner to Example 378, step 2. Product isolated as a solid (0.3 g, 87%).Analysis: LCMS m/z 345 (M+1).

Step 4

The title product was prepared from2-[2-methyl-4′-(piperidin-4-yloxy)-biphenyl-3-yl]-pyridine (110 mg, 0.32mmol) and propanoyl chloride (50 uL, 0.5 mmol) in an analogous manner toExample 378 step 3. Product isolated as a solid (0.07 g, 40%). Analysis:LCMS m/z=401 (M+1). ¹H NMR (DMSO-d6) δ: 8.78 (d, 1H, J=4.5 Hz), 8.17 (m,1H), 7.78 (d, 1H, J=7.8 Hz), 7.63 (m, 1H), 7.39 (m, 2H), 7.30 (m, 3H),7.08 (d, 2H, J=8.6 Hz), 4.66 (m, 1H), 3.90 (m, 1H), 3.71 (m, 1H), 3.33(m, 1H), 3.24 (m, 1H), 2.33 (m, 2H), 2.12 (s, 3H), 1.96 (m, 2H),1.51-1.63 (br m, 2H), 0.99 (t, 3H, J=7.4 Hz).

Example 407.Cyclopropyl-[4-(2′-methyl-3′-pyridin-2-yl-biphenyl-4-yloxy)-piperidin-1-yl]-methanone,TFA salt

The title compound was prepared from2-[2-methyl-4′-(piperidin-4-yloxy)-biphenyl-3-yl]-pyridine (110 mg, 0.32mmol) and cyclopropanecarbonyl chloride (50 μL, 0.5 mmol) in ananalogous manner to Example 378 step 3. Product isolated as a solid(0.14 g, 80%). Analysis: LCMS m/z=413 (M+1). ¹H NMR (DMSO-d6) δ: 8.78(d, 1H, J=4.5 Hz), 8.17 (m, 1H), 7.78 (d, 1H, J=7.8 Hz), 7.63 (m, 1H),7.39 (m, 2H), 7.30 (m, 3H), 7.08 (d, 2H, J=8.6 Hz), 4.68 (m, 1H), 3.99(m, 1H), 3.90 (m, 1H), 3.54 (m, 1H), 3.26 (m, 1H), 2.12 (s, 3H), 2.00(br m, 3H), 1.54-1.64 (br m, 2H), 0.71 (m, 4H).

Example 408.Cyclobutyl-[4-(2′-methyl-3′-pyridin-2-yl-biphenyl-4-yloxy)-piperidin-1-yl]-methanone,TFA salt

The title compound was prepared from2-[2-methyl-4′-(piperidin-4-yloxy)-biphenyl-3-yl]-pyridine (110 mg, 0.32mmol) and cyclobutanecarbonyl chloride (60 uL, 0.5 mmol) in an analogousmanner to Example 378 step 3. Product isolated as a solid (0.08 g, 43%).Analysis: LCMS m/z=427 (M+1). ¹H NMR (DMSO-d6) δ: 8.78 (d, 1H, J=4.5Hz), 8.17 (m, 1H), 7.78 (d, 1H, J=7.8 Hz), 7.63 (m, 1H), 7.39 (m, 2H),7.30 (m, 3H), 7.08 (d, 2H, J=8.6 Hz), 4.65 (m, 1H), 3.90 (m, 1H), 3.57(m, 1H), 3.36 (m, 1H), 3.23 (m, 2H), 2.15 (m, 2H), 2.11 (s, 3H), 2.09(m, 2H), 1.93 (m, 3H), 1.74 (m, 1H), 1.53 (m, 2H).

Example 409.1-{4-[4-(2-Phenoxypyridin-4-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1

4-[4-(2-Fluoropyridin-4-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester was prepared from4-(4-iodophenoxy)-piperidine-1-carboxylic acid t-butyl ester (0.5 g,1.24 mmol) and 2-fluoropyridine-4-boronic acid (0.26 g, 1.86 mmol) in ananalogous manner to Example 378. Product isolated as a solid (0.2 g,44%). Analysis: LCMS m/z 373 (M+1).

Step 2

2-Fluoro-4-[4-(piperidin-4-yloxy)-phenyl]-pyridine was prepared from4-[4-(2-fluoropyridin-4-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester (0.2 g, 0.55 mmol) and trifluoroacetic acid (1 mL) inan analogous manner to Example 378 step 2. Product isolated as a solid(0.15 g, 98%). Analysis: LCMS m/z 273 (M+1).

Step 3

Phenol (59 mg, 0.63 mmol) in DMF (5 mL) at 0° C. was added NaH, 60%disp. in mineral oil (65 mg, 1.62 mmol). After stirring 0.5 h at rt,1-{4-[4-(2-fluoropyridin-4-yl)-phenoxy]-piperidin-1-yl}-propan-1-one(0.17 g, 0.52 mmol) was added dropwise in DMF (2 mL) and the reactionwas stirred at 100° C. overnight. The reaction was diluted with EtOAc,was washed with water/brine, dried over Na₂SO₄, and concentrated. Theproduct was purified using the Gilson (0.1% TFA in water/0. 1% TFA inacetonitrile gradient). The clean fractions were diluted with DCM,washed with 1N Na₂CO₃/water/brine, dried over Na₂SO₄, concentrated, anddried under high vacuum at 50° C. overnight.1-{4-[4-(2-phenoxy-pyridin-4-yl)-phenoxy]-piperidin-1-yl}-propan-1-onewas isolated as a solid (0.05 g, 21%). Analysis: LCMS m/z=403 (M+1). ¹HNMR (DMSO-d6) δ: 8.15 (d, 1H, J=5.3 Hz), 7.79 (m, 2H), 7.42 (m, 3H),7.30 (s, 1H), 7.21 (m, 1H), 7.13 (m, 4H), 4.71 (m, 1H), 3.90 (m, 1H),3.70 (m, 1H), 3.35 (m, 1H), 3.25 (m, 1H), 2.33 (m, 2H), 1.97 (br m, 2H),1.50-1.62 (br m, 2H), 0.99 (t, 3H, J=7.3 Hz).

Example 410.1-{4-[4-(4-Methoxypyrazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,HCl

Step 1

6-Bromopyrazolo[1,5-a]pyridin-4-ol (0.5 g, 2.35 mmol) in DMF (5 mL)under an atmosphere of nitrogen was added cesium carbonate (2.3 g, 7.04mmol), followed by methyl iodide (0.22 mL, 3.52 mmol) and the reactionwas heated at 80° C. for 1 h. The reaction was cooled at rt, dilutedwith ethyl acetate, washed with water several times, washed with brine,dried over sodium sulfate, and concentrated. The product was purifiedvia silica gel chromatography (10% ethyl acetate/hexanes) andconcentrated. 6-Bromo-4-methoxy-pyrazolo[1,5-a]pyridine was isolated asa solid (0.43 g, 80%). Analysis: LCMS m/z=228 (M+1).

Step 2

4-[4-(4-Methoxypyrazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and6-bromo-4-methoxy-pyrazolo[1,5-a]pyridine (0.42 g, 1.86 mmol) in ananalogous manner to Example 378. Product isolated as a solid (0.4 g,78%). Analysis: LCMS m/z 424 (M+1).

Step 3

4-Methoxy-6-[4-(piperidin-4-yloxy)-phenyl]-pyrazolo[1,5-a]pyridine wasprepared from4-[4-(4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (0.4 g, 0.97 mmol) and TFA (2 mL) in an analogousmanner to Example 378 step 2. Product isolated as a solid (0.25 g, 79%).Analysis: LCMS m/z 324 (M+1).

Step 4

The title compound was prepared from4-methoxy-6-[4-(piperidin-4-yloxy)-phenyl]-pyrazolo[1,5-a]pyridine (82mg, 0.25 mmol) and propanoyl chloride (40 uL, 0.4 mmol) in an analogousmanner to Example 398. Product isolated as a solid (0.07 g, 62%).Analysis: LCMS m/z=380 (M+1). ¹H NMR (DMSO-d6) δ: 8.57 (s, 1H), 7.94 (d,1H, J=2.2 Hz), 7.73 (d, 2H, J=8.7 Hz), 7.51 (br m, 1H), 7.10 (d, 2H,J=8.8 Hz), 6.89 (s, 1H), 6.62 (m, 1H), 4.69 (m, 1H), 4.03 (s, 3H), 3.85(m, 1H), 3.68 (m, 1H), 3.35 (br m, 2H), 2.33 (m, 2H), 1.96 (m, 2H),1.51-1.63 (br m, 2H), 0.99 (t, 3H, J=7.3 Hz).

Example 411.Cyclopropyl-{4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone,HCl

This example was prepared from4-methoxy-6-[4-(piperidin-4-yloxy)-phenyl]-pyrazolo[1,5-a]pyridine (82mg, 0.25 mmol) and cyclopropanecarbonyl chloride (40 uL, 0.4 mmol) in ananalogous manner to Example 398. Product isolated as a solid (0.08 g,72%). Analysis: LCMS m/z=392 (M+1). ¹H NMR (DMSO-d6) δ: 8.57 (s, 1H),7.94 (d, 1H, J=2.2 Hz), 7.73 (d, 2H, J=8.7 Hz), 7.10 (d, 2H, J=8.8 Hz),6.89 (s, 1H), 6.62 (m, 1H), 4.71 (m, 1H), 4.20 (br m, 1H), 4.02 (s, 3H),3.97 (m, 1H), 3.87 (m, 1H), 3.56 (m, 1H), 3.29 (m, 1H), 2.00 (br m, 3H),1.54-1.64 (br m, 2H), 0.71 (m, 4H).

Example 412.Cyclobutyl-{4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone,HCl

This example was prepared from4-methoxy-6-[4-(piperidin-4-yloxy)-phenyl]-pyrazolo[1,5-a]pyridine (82mg, 0.25 mmol) and cyclobutanecarbonyl chloride (50 uL, 0.4 mmol) in ananalogous manner to Example 398. Product isolated as a solid (0.04 g,36%). Analysis: LCMS m/z=406 (M+1). ¹H NMR (DMSO-d6) δ: 8.57 (s, 1H),7.94 (d, 1H, J=2.2 Hz), 7.73 (d, 2H, J=8.7 Hz), 7.10 (d, 2H, J=8.8 Hz),6.89 (s, 1H), 6.62 (m, 1H), 4.70 (m, 1H), 4.45 (br m, 1H), 4.02 (s, 3H),3.88 (m, 1H), 3.59 (m, 1H), 3.36 (m, 1H), 3.26 (m, 2H), 2.07-2. 51 (brm, 7H), 1.74 (m, 1H), 1.55 (m, 2H).

Example 413.1-{4-[4-(3-Chloroisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1

4-[4-(3-Chloroisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and 6-bromo-3-chloro-isoquinoline(0.3 g, 1.24 mmol) in an analogous manner to Example 378. Productisolated as a solid (0.47 g, 87%). Analysis: LCMS m/z 439 (M+1).

Step 2

3-Chloro-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline was prepared from4-[4-(3-chloro-isoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester (0.23 g, 0.52 mmol) and trifluoroacetic acid (1 mL) inan analogous manner to Example 378 step 2. Product isolated as a solid(0.15 g, 86%). Analysis: LCMS m/z 339 (M+1).

Step 3

The title compound was prepared from3-chloro-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (75 mg, 0.22mmol) and propanoyl chloride (30 uL, 0.4 mmol) in an analogous manner toExample 396. Product isolated as a solid (0.03 g, 34%). Analysis: LCMSm/z=395 (M+1). ¹H NMR (DMSO-d6) δ: 9.19 (s, 1H), 8.21 (m, 2H), 8.03 (m,2H), 7.80 (m, 2H), 7.15 (m, 2H), 4.72 (m, 1H), 3.88 (m, 1H), 3.69 (m,1H), 3.35 (m, 1H), 3.27 (m, 1H), 2.35 (m, 2H), 1.97 (br m, 2H),1.52-1.64 (br m, 2H), 1.00 (t, 3H, J=7.3 Hz).

Example 414.{4-[4-(3-Chloroisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-cyclopropyl-methanone

This example was prepared from3-chloro-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (75 mg, 0.22mmol) and cyclopropanecarbonyl chloride (30 uL, 0.4 mmol) in ananalogous manner to Example 396. Product isolated as a solid (0.05 g,56%). Analysis: LCMS m/z=407 (M+1). ¹H NMR (DMSO-d6) δ: 9.19 (s, 1H),8.21 (m, 2H), 8.03 (m, 2H), 7.80 (m, 2H), 7.15 (m, 2H), 4.75 (m, 1H),4.02 (m, 1H), 3.89 (m, 1H), 3.56 (m, 1H), 3.29 (m, 1H), 2.00 (br m, 3H),1.56-1.66 (br m, 2H), 0.71 (m, 4H).

Example 415.1-{4-[4-(3-Methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1

4-[4-(3-Methoxy-isoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.57 g, 1.40 mmol) and6-bromo-3-methoxy-isoquinoline (0.5 g, 2.10 mmol) in an analogous mannerto Example 378. Product isolated as a solid (0.51 g, 84%). Analysis:LCMS m/z 435 (M+1).

Step 2

3-Methoxy-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline was preparedfrom 4-[4-(3-methoxy-isoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (0.51 g, 1.2 mmol) and TFA (2 mL) in an analogousmanner to Example 378 step 2. Product isolated as a solid (0.36 g, 91%).Analysis: LCMS m/z 335 (M+1).

Step 3

The title compound was prepared from3-methoxy-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (89 mg, 0.27mmol) and propanoyl chloride (40 uL, 0.4 mmol) in an analogous manner toExample 379. Product isolated as a solid (0.06 g, 58%). Analysis: LCMSm/z=391 (M+1). ¹H NMR (DMSO-d6) δ: 9.04 (s, 1H), 8.04 (m, 2H), 7.95 (m,3H), 7.20 (s, 1H), 7.14 (m, 2H), 4.71 (m, 1H), 3.95 (s, 3H), 3.87 (m,1H), 3.69 (m, 1H), 3.35 (m, 1H), 3.26 (m, 1H), 2.35 (m, 2H), 1.98 (br m,2H), 1.52-1.64 (br m, 2H), 0.99 (t, 3H, J=7.4 Hz).

Example 416.Cyclopropyl-{4-[4-(3-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone

This example was synthesized from3-methoxy-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (89 mg, 0.27mmol) and cyclopropanecarbonyl chloride (40 uL, 0.4 mmol) in ananalogous manner to Example 396. Product isolated as a solid (0.08 g,75%). Analysis: LCMS m/z=403 (M+1). ¹H NMR (DMSO-d6) δ: 9.04 (s, 1H),8.04 (m, 2H), 7.75 (m, 3H), 7.20 (s, 1H), 7.14 (m, 2H), 4.73 (m, 1H),4.00 (m, 1H), 3.95 (s, 3H), 3.90 (m, 1H), 3.56 (m, 1H), 3.29 (m, 1H),2.00 (br m, 3H), 1.65 (br m, 2H), 0.74 (m, 4H).

Example 417.Cyclobutyl-{4-[4-(3-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone

This example was synthesized from3-methoxy-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (89 mg, 0.27mmol) and cyclobutanecarbonyl chloride (50 uL, 0.4 mmol) in an analogousmanner to Example 396. Product isolated as a solid (0.08 g, 68%).Analysis: LCMS m/z=417 (M+1). ¹H NMR (DMSO-d6) δ: 9.04 (s, 1H), 8.04 (m,2H), 7.95 (m, 3H), 7.20 (s, 1H), 7.14 (m, 2H), 4.69 (m, 1H), 3.95 (s,3H), 3.85 (m, 1H), 3.56 (m, 1H), 3.36 (m, 1H), 3.25 (m, 2H), 2.17 (br m,4H), 1.92 (br m, 3H), 1.75 (m, 1H), 1.53 (m, 2H).

Example 418.{4-[4-(3-Methoxy-isoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

To 3-ethoxy-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (0.09 g, 0.27mmol) in DMF (3 mL) was added HATU (0.15 g, 0.4 mmol), DIPEA (0.14 mL,0.8 mmol), followed by (R)-tetrahydrofuran-2-carboxylic acid (0.05 mL,0.53 mmol) and the mixture was stirred at rt for 1 h. The mixture waspoured into ethyl acetate, washed with 1N sodium carbonate/brine, driedover sodium sulfate, and concentrated. The product was purified usingthe Gilson (0.1% TFA in water/0. 1% TFA in acetonitrile gradient),diluted clean fractions with DCM, washed with 1N sodium carbonate/brine,dried over sodium sulfate, and concentrated.{4-[4-(3-Methoxy-isoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanonewas isolated as a solid (0.09 g, 74%). Analysis: LCMS m/z=433 (M+1). ¹HNMR (DMSO-d6) δ: 9.04 (s, 1H), 8.04 (m, 2H), 7.95 (m, 3H), 7.20 (s, 1H),7.14 (m, 2H), 4.69 (m, 2H), 3.95 (s, 3H), 3.77 (m, 4H), 3.42 (m, 2H),2.01 (br m, 4H), 1.84 (m, 2H), 1.63 (m, 2H).

Example 419.1-{4-[4-(1-Chloroisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1

4-[4-(1-Chloroisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and 6-bromo-1-chloro-isoquinoline(0.3 g, 1.24 mmol) in an analogous manner to Example 378. Productisolated as a solid (0.2 g, 36%). Analysis: LCMS m/z 439 (M+1).

Step 2

1-Chloro-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline was prepared from4-[4-(1-chloroisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester (0.2 g, 0.45 mmol) and TFA (1 mL) in an analogousmanner to Example 378 step 2. Product isolated as a solid (0.14 g, 93%).Analysis: LCMS m/z 339 (M+1).

Step 3

The title compound was prepared from1-chloro-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (70 mg, 0.2 mmol)and propanoyl chloride (30 uL, 0.4 mmol) in an analogous manner toExample 379. Product isolated as a solid (0.04 g, 40%). Analysis: LCMSm/z=395 (M+1). ¹H NMR (DMSO-d6) δ: 8.31 (m, 3H), 8.15 (m, 1H), 7.93 (m,1H), 7.84 (m, 2H), 7.18 (m, 2H), 4.73 (m, 1H), 3.87 (m, 1H), 3.69 (m,1H), 3.35 (m, 1H), 3.27 (m, 1H), 2.34 (m, 2H), 1.98 (br m, 2H),1.52-1.64 (br m, 2H), 1.00 (t, 3H, J=7.4 Hz).

Example 420.{4-[4-(1-Chloroisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-cyclopropyl-methanone

This example was synthesized from1-chloro-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (70 mg, 0.2 mmol)and cyclopropanecarbonyl chloride (30 uL, 0.4 mmol) in an analogousmanner to Example 396. Product isolated as a solid (0.04 g, 50%).Analysis: LCMS m/z=407 (M+1). ¹H NMR (DMSO-d6) δ: 8.31 (m, 3H), 8.15 (m,1H), 7.93 (m, 1H), 7.84 (m, 2H), 7.18 (m, 2H), 4.75 (m, 1H), 3.99 (m,1H), 3.89 (m, 1H), 3.56 (m, 1H), 3.29 (m, 1H), 2.04 (br m, 3H),1.55-1.65 (br m, 2H), 0.74 (m, 4H).

Example 421.1-{4-[4-(3-Dimethylaminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1

4-[4-(3-Chloroisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and 6-bromo-3-chloroisoquinoline(0.3 g, 1.24 mmol) in an analogous manner to Example 378. Productisolated as a solid (0.47 g, 87%). Analysis: LCMS m/z 439 (M+1).

Step 2

To an oven dried flask under an atmosphere of argon was added4-[4-(3-chloroisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester (0.2 g, 0.46 mmol), 2M of dimethylamine in THF (0.68 mL,1.37 mmol), cinnamylpalladium chloride dimer (24 mg, 0.05 mmol),di(1-adamantyl)-2-dimethylaminophenylphosphine (38 mg, 0.09 mmol),sodium t-butoxide (0.13 g, 1.37 mmol), followed by toluene (40 mL) andthe reaction was degassed 3 times under an atmosphere of argon and wasstirred at 90° C. overnight. Cooled at rt, diluted with DCM, filteredthrough a pad of celite, washed with water/brine, dried over sodiumsulfate, and concentrated. The product was purified via silica gelchromatography (10-20% EtOAc/hexanes) and concentrated.4-[4-(3-Dimethylamino-isoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester was isolated as a solid (0.1 g, 53%). Analysis: LCMSm/z 448 (M+1).

Step 3

Dimethyl-{6-[4-(piperidin-4-yloxy)-phenyl]-isoquinolin-3-yl}-amine wasprepared from4-[4-(3-dimethylamino-isoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (0.1 g, 0.24 mmol) and TFA (1 mL) in an analogousmanner to Example 378 step 2. Product isolated as a solid (0.08 g, 92%).Analysis: LCMS m/z 348 (M+1).

Step 4

The title compound was prepared fromdimethyl-{6-[4-(piperidin-4-yloxy)-phenyl]-isoquinolin-3-yl}-amine (76mg, 0.22 mmol) and propanoyl chloride (30 uL, 0.4 mmol) in an analogousmanner to Example 396. Product isolated as a solid (0.04 g, 45%).Analysis: LCMS m/z=404 (M+1). ¹H NMR (DMSO-d6) δ: 8.92 (s, 1H), 7.84 (m,2H), 7.71 (m, 2H), 7.50 (m, 1H), 7.12 (d, 2H, J=8.8 Hz), 6.79 (s, 1H),4.69 (m, 1H), 3.90 (m, 1H), 3.69 (m, 1H), 3.37 (m, 1H), 3.29 (m, 1H),3.11 (s, 6H), 2.35 (m, 2H), 1.98 (br m, 2H), 1.51-1.64 (br m, 2H), 0.99(t, 3H, J=7.3 Hz).

Example 422.1-{4-[4-(3-Aminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1

4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidinewas prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.3 g, 0.74 mmol) and TFA (1 mL) in an analogousmanner to Example 378 step 2. Product isolated as a solid (0.2 g, 87%).Analysis: LCMS m/z 304 (M+1).

Step 2

1-{4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidin-1-yl}-propan-1-onewas prepared from the Step 1 product (97 mg, 0.32 mmol) and propanoylchloride (50 uL, 0.5 mmol) in an analogous manner to Example 378 step 3.Product isolated as a solid (0.11 g, 97%). Analysis: LCMS m/z=360 (M+1).

Step 3

1-{4-[4-(3-Aminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-onewas prepared from the Step 2 product (0.11 g, 0.32 mmol) and6-bromoisoquinolin-3-ylamine (0.11 g, 0.48 mmol) in an analogous mannerto Example 378. Product isolated as a solid (0.05 g, 42%). Analysis:LCMS m/z=376 (M+1). ¹H NMR (DMSO-d6) δ: 8.78 (s, 1H), 7.84 (d, 1H, J=8.6Hz), 7.70 (m, 3H), 7.44 (m, 1H), 7.11 (m, 2H), 6.65 (s, 1H), 5.91 (s,2H), 4.69 (m, 1H), 3.88 (m, 1H), 3.69 (m, 1H), 3.34 (m, 1H), 3.29 (m,1H), 2.33 (m, 2H), 1.96 (br m, 2H), 1.50-1.64 (br m, 2H), 0.99 (t, 3H,J=7.3 Hz).

Example 423.{4-[4-(3-Aminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-cyclopropyl-methanone

Step 1

Cyclopropyl-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidin-1-yl}-methanonewas prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine(97 mg, 0.32 mmol) and cyclopropanecarbonyl chloride (50 uL, 0.5 mmol)in an analogous manner to Example 378 step 3. Product isolated as asolid (0.12 g, 100%). Analysis: LCMS m/z=372 (M+1).

Step 2

The title compound was prepared form the Step 2 product (0.13 g, 0.35mmol) and 6-bromoisoquinolin-3-ylamine (0.12 g, 0.52 mmol) in ananalogous manner to Example 378. Product isolated as a solid (0.07 g,52%). Analysis: LCMS m/z=388 (M+1). ¹H NMR (DMSO-d6) δ: 8.78 (s, 1H),7.84 (d, 1H, J=8.6 Hz), 7.70 (m, 3H), 7.44 (m, 1H), 7.11 (m, 2H), 6.65(s, 1H), 5.91 (s, 2H), 4.71 (m, 1H), 3.98 (m, 1H), 3.88 (m, 1H), 3.56(m, 1H), 3.29 (m, 1H), 2.00 (br m, 3H), 1.54-1.64 (br m, 2H), 0.71 (m,4H).

Example 424.{4-[4-(4-Methoxypyrazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone,HCl

To 4-methoxy-6-[4-(piperidin-4-yloxy)-phenyl]-pyrazolo[1,5-a]pyridine(0.09 g, 0.28 mmol) in DMF (3 mL) was added HATU (0.16 g, 0.42 mmol),DIPEA (0.15 mL, 0.84 mmol), followed by (R)-tetrahydrofuran-2-carboxylicacid (0.05 mL, 0.56 mmol) and was stirred at rt for 1 h. The solutionwas poured into EtOAc, washed with 1N Na₂CO₃/brine, dried over sodiumsulfate, and concentrated. The product was purified using the Gilson(0.1% TFA in water/0.1% TFA in acetonitrile gradient), diluted cleanfractions with DCM, washed with 1N Na₂CO₃/brine, dried over sodiumsulfate, and concentrated. Dissolved compound in DCM, 2 M of HCl indiethyl ether (0.14 mL, 0.28 mmol) was added and concentrated. Driedsample under high vacuum at 40° C. overnight.{4-[4-(4-Methoxypyrazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone;HCl was isolated as a solid (0.03 g, 24%). Analysis: LCMS m/z=422 (M+1).¹H NMR (DMSO-d6) δ: 8.57 (s, 1H), 7.94 (d, 1H, J=2.2 Hz), 7.73 (m, 2H),7.10 (d, 2H, J=8.7 Hz), 6.89 (s, 1H), 6.62 (m, 1H), 4.68 (m, 2H), 4.02(s, 3H), 3.78 (m, 4H), 3.37 (m, 1H), 3.25 (m, 1H), 1.80-2.08 (br m, 6H),1.53-1.65 (br m, 2H).

Example 425.1-{4-[4-(1-Methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1

4-[4-(1-Chloroisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and 6-bromo-1-chloroisoquinoline(0.3 g, 1.24 mmol)) in an analogous manner to Example 378. Productisolated as a solid (0.14 g, 26%). Analysis: LCMS m/z 439 (M+1).

Step 2

To an oven dried schlenck flask under an atmosphere of argon was added4-[4-(1-chloroisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester (0.14 g, 0.32 mmol), methylboronic acid (96 mg, 1.59mmol), DPPF-Pd(II) complex with DCM (1:1) (52 mg, 0.06 mmol), potassiumphosphate (338 mg, 1.59 mmol), followed by 1,4-dioxane (5 mL) and wasdegassed under an atmosphere of argon for 5 min and was heated at 99° C.overnight. The reaction was cooled, filtered through a pad of celite,washed with 1N sodium carbonate/water/brine, dried over sodium sulfate,and concentrated. The product was purified via silica gel chromatography(10-50% ethyl acetate/hexanes) and concentrated.4-[4-(1-methyl-isoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was isolated as a solid (0.06 g, 46%). Analysis: LCMS m/z419 (M+1).

Step 3

1-Methyl-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline was prepared from4-[4-(1-methyl-isoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester (0.06 g, 0.14 mmol) and trifluoroacetic acid (1 mL) inan analogous manner to Example 378. Product isolated as a solid (0.05 g,100%). Analysis: LCMS m/z 319 (M+1).

Step d

The title compound was prepared from the Step 3 product (60 mg, 0.2mmol) and propanoyl chloride (30 uL, 0.4 mmol) in an analogous manner toExample 396. Product isolated as a solid (0.03 g). Analysis: LCMSm/z=375 (M+1). ¹H NMR (DMSO-d6) δ: 8.34 (d, 1H, J=5.7 Hz), 8.23 (m, 1H),8.17 (m, 1H), 7.98 (m, 1H), 7.81 (m, 2H), 7.70 (m, 1H), 7.13 (m, 2H),4.71 (m, 1H), 3.87 (m, 1H), 3.69 (m, 1H), 3.35 (m, 1H), 3.29 (m, 1H),2.89 (s, 3H), 2.35 (m, 2H), 1.98 (br m, 2H), 1.52-1.65 (br m, 2H), 1.00(t, 3H, J=7.3 Hz).

Example 426.1-{4-[4-(4-Hydroxypyrazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

This example was synthesized from1-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidin-1-yl}-propan-1-one(0.1 g, 0.28 mmol) and 6-bromo-pyrazolo[1,5-a]pyridin-4-ol (89 mg, 0.42mmol) in an analogous manner to Example 378. Product isolated as a solid(0.03 g, 29%). Analysis: LCMS m/z=366 (M+1). ¹H NMR (DMSO-d6) δ: 10.61(s, 1H), 8.46 (m, 1H), 7.89 (d, 1H, J=2.2 Hz), 7.60 (m, 2H), 7.08 (m,2H), 6.72 (m, 1H), 6.63 (m, 1H), 4.66 (m, 1H), 3.89 (m, 1H), 3.72 (m,1H), 3.35 (m, 1H), 3.25 (m, 1H), 2.33 (m, 2H), 1.95 (br m, 2H),1.48-1.62 (br m, 2H), 0.99 (t, 3H, J=7.3 Hz).

Example 427.Cyclobutyl-{4-[4-(4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone

Cyclobutyl-{4-[4-(4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-phenoxy]-piperidin-1-yl}-methanone1-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidin-1-yl}-propan-1-one(0.1 g, 0.28 mmol) and 6-bromo-pyrazolo[1,5-a]pyridin-4-ol (91 mg, 0.43mmol) in an analogous manner to Example 378. Product isolated as a solid(0.04 g, 37%). Analysis: LCMS m/z=392 (M+1). ¹H NMR (DMSO-d₆) δ: 10.61(s, 1H), 8.46 (m, 1H), 7.89 (d, 1H, J=2.2 Hz), 7.60 (m, 2H), 7.08 (m,2H), 6.72 (m, 1H), 6.63 (m, 1H), 4.65 (m, 1H), 3.85 (m, 1H), 3.55 (m,1H), 3.36 (m, 1H), 3.24 (m, 2H), 2.14 (m, 4H), 1.92 (m, 3H), 1.74 (m,1H), 1.54 (m, 2H).

Example 428.{4-[4-(1-Chloroisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-cyclobutyl-methanone

This example was synthesized from1-chloro-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (40 mg, 0.1 mmol)and cyclobutanecarbonyl chloride (20 uL, 0.2 mmol) in an analogousmanner to Example 379. Product isolated as a solid (0.03 g, 50%).Analysis: LCMS m/z=421 (M+1). ¹H NMR (DMSO-d6) δ: 8.31 (m, 3H), 8.15 (m,1H), 7.93 (m, 1H), 7.84 (m, 2H), 7.18 (m, 2H), 4.72 (m, 1H), 3.85 (m,1H), 3.56 (m, 1H), 3.36 (m, 1H), 3.29 (m, 2H), 2.17 (m, 2H), 2.09 (m,2H), 1.93 (m, 3H), 1.74 (m, 1H), 1.56 (m, 2H).

Example 429.{4-[4-(1-Chloroisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone

This example was synthesized from1-chloro-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (0.04 g, 0.12mmol) and (R)-tetrahydrofuran-2-carboxylic acid (0.02 mL, 0.24 mmol) inan analogous manner to Example 418. Product isolated as a solid (0.02 g,39%). Analysis: LCMS m/z=437 (M+1). ¹H NMR (DMSO-d6) δ: 8.31 (m, 3H),8.15 (m, 1H), 7.93 (m, 1H), 7.84 (m, 2H), 7.18 (m, 2H), 4.75 (m, 1H),4.69 (m, 1H), 3.77 (m, 4H), 3.34 (m, 1H), 3.29 (m, 1H), 2.01 (m, 4H),1.84 (m, 2H), 1.52-1.65 (br m, 2H).

Example 430.1-{4-[4-(3-Methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1

To an oven-dried schlenck flask under an atmosphere of argon was added4-[4-(3-chloroisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester (0.44 g, 1 mmol), methylboronic acid (301 mg, 5.02 mmol),amphos (142 mg, 0.2 mmol), cesium carbonate (1.64 g, 5.02 mmol),followed by 1,4-dioxane (60 mL) and was degassed under an atmosphere ofargon for 5 min and was heated at 99° C. overnight. The reaction wascooled, filtered through a pad of celite, washed with 1N sodiumcarbonate, water, brine, dried over sodium sulfate, and concentrated.The product was purified via silica gel chromatography (10-30% ethylacetate/hexanes) and concentrated.4-[4-(3-methyl-isoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester was isolated as a solid (0.11 g, 27%). Analysis: LCMSm/z=419 (M+1).

Step 2

3-Methyl-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline was prepared from4-[4-(3-methylisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester (0.11 g, 0.27 mmol) and trifluoroacetic acid (1 mL) inan analogous manner to Example 378. Product isolated as a solid (0.08 g,87%). Analysis: LCMS m/z=319 (M+1).

Step 3

The title compound was prepared from3-methyl-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (75 mg, 0.24 mmo)and propanoyl chloride (30 uL, 0.4 mmol) in an analogous manner toExample 396. Product isolated as a solid (0.05 g, 51%). Analysis: LCMSm/z=375 (M+1). ¹H NMR (DMSO-d6) δ: 9.20 (s, 1H), 8.12 (d, 1H, J=8.6 Hz),8.07 (s, 1H), 7.90 (m, 1H), 7.78 (m, 2H), 7.66 (s, 1H), 7.15 (d, 2H,J=8.8 Hz), 4.71 (m, 1H), 3.88 (m, 1H), 3.73 (m, 1H), 3.36 (m, 1H), 3.29(m, 1H), 2.61 (s, 3H), 2.33 (m, 2H), 1.98 (br m, 2H), 1.52-1.64 (br, m,2H), 0.99 (t, 3H, J=7.4 Hz).

Example 431.{4-[4-(1-Methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone

This example was synthesized from1-methyl-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (50 mg, 0.2 mmol)and (R)-tetrahydrofuran-2-carboxylic acid (30 uL, 0.31 mmol) in ananalogous manner to Example 639. Product isolated as a solid. Analysis:LCMS m/z=417 (M+1). ¹H NMR (DMSO-d6) δ: 8.34 (d, 1H, J=5.8 Hz), 8.25 (d,1H, J=8.7 Hz), 8.18 (m, 1H), 7.98 (m, 1H), 7.81 (d, 2H. J=8.7 Hz), 7.70(d, 1H, J=5.8 Hz), 7.16 (d, 2H, J=8.7 Hz), 4.69 (m, 2H), 3.77 (m, 4H),3.43 (m, 1H), 3.26 (m, 1H), 2.89 (s, 3H), 2.01 (br m, 4H), 1.84 (m, 2H),1.52-1.66 (br m, 2H).

Example 432.{4-[4-(1-Methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Step 1

4-[4-(1-Methoxyisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and 6-bromo-1-methoxy-isoquinoline(443 mg, 1.86 mmol) in an analogous manner to Example 378. Productisolated as a solid. Analysis: LCMS m/z=435 (M+1).

Step 2

1-Methoxy-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline was preparedfrom the step 1 product and trifluoroacetic acid (2 mL) in an analogousmanner to Example 378. Product isolated as a solid. Analysis: LCMSm/z=335 (M+1).

Step 3

The title compound was prepared from1-methoxy-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (0.09 g, 0.27mmol) and (R)-tetrahydrofuran-2-carboxylic acid (0.05 mL, 0.53 mmol) inan analogous manner to Example 418. Product isolated as a solid (0.04 g,30%). Analysis: LCMS m/z=433 (M+1). ¹H NMR (DMSO-d6) δ: 8.21 (d, 1H,J=8.7 Hz), 8.13 (s, 1H), 8.02 (d, 1H, J=5.8 Hz), 7.92 (m, 1H), 7.79 (d,2H, J=8.7 Hz), 7.43 (d, 1H, J=5.7 Hz), 7.15 (d, 2H, J=8.7 Hz), 4.73 (m,2H), 4.07 (s, 3H), 3.75 (br m, 4H), 3.42 (m, 1H), 3.25 (m, 1H), 2.01 (brm, 4H), 1.84 (m, 2H), 1.54-1.66 (br m, 2H).

Example 433.1-{4-[4-(1-Methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

This example was synthesized from1-methoxy-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (0.09 g, 0.27mmol) and propanoyl chloride (40 uL, 0.4 mmol) in an analogous manner toExample 379. Product isolated as a solid (0.06 g, 53%). Analysis: LCMSm/z=391 (M+1). ¹H NMR (DMSO-d6) δ: 8.21 (d, 1H, J=8.7 Hz), 8.13 (s, 1H),8.02 (d, 1H, J=5.8 Hz), 7.92 (m, 1H), 7.79 (d, 2H, J=8.7 Hz), 7.43 (d,1H, J=5.7 Hz), 7.15 (d, 2H, J=8.7 Hz), 4.71 (m, 1H), 4.07 (s, 3H), 3.88(m, 1H), 3.72 (m, 1H), 3.35 (m, 1H), 3.26 (m, 1H), 2.33 (m, 2H), 1.98(br m, 2H), 1.52-1.64 (br m, 2H), 0.99 (t, 3H, J=7.4 Hz).

Example 434.Cyclobutyl-{4-[4-(1-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone

This example was synthesized from1-methoxy-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (0.09 g, 0.27mmol) and cyclobutanecarbonyl chloride (50 uL, 0.4 mmol) in an analogousmanner to Example 396. Product isolated as a solid (0.07 g, 60%).Analysis: LCMS m/z=417 (M+1). ¹H NMR (DMSO-d6) δ: 8.21 (d, 1H, J=8.7Hz), 8.13 (s, 1H), 8.02 (d, 1H, J=5.8 Hz), 7.92 (m, 1H), 7.79 (d, 2H,J=8.7 Hz), 7.43 (d, 1H, J=5.7 hZ), 7.15 (d, 2H, J=8.7 Hz), 4.70 (m, 1H),4.07 (m, 3H), 3.88 (m, 1H), 3.56 (m, 1H), 3.36 (m, 1H), 3.25 (m, 2H),2.07-2.20 (br m, 4H), 1.92 (br m, 3H), 1.74 (m, 1H), 1.56 (m, 2H).

Example 435.Cyclopropyl-{4-[4-(1-methoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone

This example was synthesized from1-methoxy-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (0.09 g, 0.27mmol) and cyclopropanecarbonyl chloride (40 uL, 0.4 mmol) analogousmanner to Example 396. Product isolated as a solid (0.03 g, 29%).Analysis: LCMS m/z=403 (M+1). ¹H NMR (DMSO-d6) δ: 8.21 (d, 1H, J=8.7Hz), 8.13 (s, 1H), 8.02 (d, 1H, J=5.8 Hz), 7.92 (m, 1H), 7.79 (d, 2H,J=8.7 Hz), 7.43 (d, 1H, J=5.7 Hz), 7.15 (d, 2H, J=8.7 Hz), 4.73 (m, 1H),4.07 (s, 3H), 3.98 (m, 1H), 3.88 (m, 1H), 3.56 (m, 1H), 3.29 (m, 1H),2.00 (br m, 3H), 1.55-1.64 (br m, 2H), 0.71 (m, 4H).

Example 436.{4-[4-(3-Aminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone

Step 1

To 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]piperidine(0.09 g, 0.3 mmol) in DMF (3 mL) was added HATU (0.17 g, 0.44 mmol),DIPEA (0.15 mL, 0.88 mmol), followed by (R)-tetrahydrofuran-2-carboxylicacid (0.05 mL, 0.59 mmol) and was stirred at RT for 1 h. The solutionwas poured into ethyl acetate, washed with 1N sodium carbonate/brine,dried over sodium sulfate, and concentrated.[(2R)-tetrahydrofuran-2-yl]-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1-piperidyl]methanonewas isolated (0.05 g, 46%). Analysis: LCMS m/z=402 (M+1).

Step 2

To an oven dried schlenck flask was added[(2R)-tetrahydrofuran-2-yl]-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1-piperidyl]methanone(0.11 g, 0.26 mmol), 6-bromoisoquinolin-3-ylamine (0.09 g, 0.39 mmol),tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.03 mmol), 1N Na₂CO₃(0.79 mL, 0.79 mmol), followed by 1,4-dioxane (2 mL) and was degassedunder an atmosphere of argon for 5 min and was heated at 99° C. for 2 h.The reaction was cooled, filtered through a pad of celite, washed with1N Na₂CO₃/water/brine, dried over sodium sulfate, and concentrated. Theproduct was purified using the Gilson (0.1% TFA in water/0.1% TFA inacetonitrile gradient), diluted clean fractions with DCM, washed with 1NNa₂CO₃/brine, dried over sodium sulfate, and concentrated.{4-[4-(3-aminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanonewas isolated as a solid (0.04 g, 34%). Analysis: LCMS m/z=403 (M+1). ¹HNMR (DMSO-d6) δ: 8.78 (s, 1H), 7.84 (d, 1H, J=8.6 Hz), 7.70 (m, 3H),7.44 (m, 2H), 7.11 (m, 2H), 6.65 (s, 1H), 5.91 (s, 2H), 4.68 (m, 2H),3.76 (m, 4H), 3.41 (m, 1H), 3.29 (m, 1H), 2.01 (br m, 4H), 1.84 (m, 2H)1.51-1.65 (br m, 2H).

Example 437.{4-[4-(3-Methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone

This example was synthesized from3-methyl-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (0.14 g, 0.43mmol) and (R)-tetrahydrofuran-2-carboxylic acid (0.08 mL, 0.86 mmol) inan analogous manner to Example 418. Product isolated as a solid (0.06 g,30%). Analysis: LCMS m/z=417 (M+1). ¹H NMR (DMSO-d₆) δ: 9.20 (s, 1H),8.12 (d, 1H, J=8.6 Hz), 8.07 (s, 1H), 7.90 (m, 1H), 7.78 (m, 2H), 7.66(s, 1H), 7.15 (d, 2H, J=8.8 Hz), 4.69 (m, 2H), 3.73-3.80 (m, 4H), 3.37(m, 1H), 3.30 (m, 1H), 2.61 (s, 3H), 2.00 (br m, 4H), 1.84 (m, 2H),1.53-1.65 (br m, 2H).

Example 438.{4-[4-(1-Ethylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone,HCl

Step 1

4-[4-(1-Ethylisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from4-[4-(1-chloroisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester (0.12 g, 0.26 mmol) and ethyl boronic acid (0.1 g, 1.31mmol) in an analogous manner to Example 425 step 2. Product isolated asa solid. Analysis: LCMS m/z=433 (M+1).

Step 2

1-Ethyl-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline was prepared fromthe Step 1 product and TFA (0.8 mL) in an analogous manner to Example378. Product isolated as a solid. Analysis: LCMS m/z=333 (M+1).

Step 3

The title compound was prepared from the Step 2 product (42 mg, 0.13mmol) and (R)-tetrahydrofuran-2-carboxylic acid (24 uL, 0.25 mmol) in ananalogous manner to Example 424. Product isolated as a solid (0.04 g,59%). Analysis: LCMS m/z=431 (M+1). ¹H NMR (DMSO-d6) δ: 8.65 (d, 1H,J=9.0 Hz), 8.54 (s, 1H), 8.48 (d, 1H, J=6.4 Hz), 8.31 (d, 1H, J=8.0 Hz),8.24 (d, 1H, J=6.0 Hz), 7.94 (d, 2H, J=8.8 Hz), 7.22 (d, 2H, J=8.8 Hz),4.78 (m, 1H), 4.69 (m, 1H), 3.77 (m, 4H), 3.54 (m, 2H), 3.35 (m, 1H),3.26 (m, 1H), 2.00 (br m, 4H), 1.84 (m, 2H), 1.50-1.66 (br m, 2H), 1.43(t, 3H, J=7.5 Hz).

Example 439.1-{4-[4-(1-Cyclopropyl-isoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1.4-[4-(1-Cyclopropylisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester was prepared from4-[4-(1-chloroisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester (0.24 g, 0.55 mmol) and cyclopropyl boronic acid (0.24g, 2.76 mmol) in an analogous manner to Example 425 step 2. Productisolated as a solid (0.15 g, 61%). Analysis: LCMS m/z=445 (M+1) Step 2

1-Cyclopropyl-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline was preparedfrom the Step 1 product (0.15 g, 0.33 mmol) and TFA (2 mL) in ananalogous manner to Ex. 378. Product isolated as a solid (0.12 g, 100%).Analysis: LCMS m/z=345 (M+1).

Step 3

The title compound was prepared from1-cyclopropyl-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (59 mg, 0.17mmol) and propanoyl chloride (20 uL, 0.3 mmol) in an analogous manner toExample 379. Product isolated as a solid (0.03 g, 48%). Analysis: LCMSm/z=401 (M+1). ¹H NMR (DMSO-d6) δ: 8.56 (d, 1H, J=9.0 Hz), 8.31 (d, 1H,J=5.6 Hz), 8.17 (s, 1H), 7.99 (m, 1H), 7.82 (m, 2H), 7.61 (d, 1H, J=5.6Hz), 7.16 (m, 2H), 4.71 (m, 1H), 3.87 (m, 1H), 3.69 (m, 1H), 3.36 (m,1H), 3.27 (m, 1H), 2.94 (m, 1H), 2.35 (m, 2H), 1.98 (br m, 2H),1.53-1.65 (br m, 2H), 1.07-1.15 (m, 4H), 1.00 (t, 3H, J=7.4 Hz).

Example 440.{4-[4-(1-Cyclopropylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

This example was synthesized from1-cyclopropyl-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (59 mg, 0.17mmol) and (R)-tetrahydrofuran-2-carboxylic acid (33 uL, 0.34 mmol) in ananalogous manner to Example 418. Product isolated as a solid (0.05 g,62%). Analysis: LCMS m/z=443 (M+1). ¹H NMR (DMSO-d6) δ: 8.56 (d, 1H,J=9.0 Hz), 8.31 (d, 1H, J=5.6 Hz), 8.17 (s, 1H), 7.99 (m, 1H), 7.82 (m,2H), 7.61 (d, 1H, J=5.6 Hz), 7.16 (m, 2H), 4.69 (m, 2H), 3.77 (br m,4H), 3.36 (m, 1H), 3.29 (m, 1H), 2.94 (m, 1H), 2.01 (br m, 4H), 1.84 (m,2H), 1.53-1.66 (br m, 2H), 1.07-1.15 (br m, 4H)

Example 441.1-{4-[4-(7-Methoxy-6-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1

4-[4-(7-Methoxy-6-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (0.5 g, 1.24 mmol) and3-bromo-7-methoxy-6-methylquinoline (469 mg, 1.86 mmol) in an analogousmanner to Example 378. Product isolated as a solid (0.56 g, 100%). LCMSm/z=449 (M+1).

Step 2

The Step 1 product (0.56 g, 1.27 mmol) was dissolved in DCM (6 mL), TFA(2 mL) was added dropwise and the reaction was stirred at rt for 1 h andconcentrated. The product was partitioned between DCM/1N sodiumcarbonate, washed with brine, dried over sodium sulfate, andconcentrated. The product was dissolved DCM, 2M of hydrogen chloride indiethyl ether (1.24 mL, 2.48 mmol) was added and concentrated.4-[4-(7-Methoxy-6-methyl-quinolin-3-yl)-phenoxy]-piperidine 2HCl wasisolated as a solid (419 mg 78%). Analysis: LCMS m/z=349 (M+1).

Step 3

The title compound was prepared from the step 2 product (90 mg, 0.2mmol) and propanoyl chloride (30 uL, 0.4 mmol) in an analogous manner toExample 396. Product isolated as a solid (0.05 g, 50%). Analysis: LCMSm/z=405 (M+1). ¹H NMR (DMSO-d6) δ: 9.06 (d, 1H, J=2.3 Hz), 8.37 (d, 1H,J=2.3 Hz), 7.75 (m, 3H), 7.36 (s, 1H), 7.14 (d, 2H, J=8.7 Hz), 4.70 (m,1H), 3.96 (s, 3H), 3.87 (m, 1H), 3.69 (m, 1H), 3.36 (m, 1H), 3.29 (m,1H), 2.35 (m, 5H), 1.97 (br m, 2H), 1.52-1.64 (br m, 2H), 0.99 (t, 3H,J=7.4 Hz).

Example 442.Cyclopropyl-{4-[4-(7-methoxy-6-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

This example was synthesized from4-[4-(7-methoxy-6-methylquinolin-3-yl)-phenoxy]-piperidine, 2HCl (90 mg,0.2 mmol) and cyclopropanecarbonyl chloride (30 uL, 0.4 mmol) in ananalogous manner to Example 396. Product isolated as a solid (0.06 g,70%). Analysis: LCMS m/z=417 (M+1). ¹H NMR (DMSO-d6) δ: 9.06 (d, 1H,J=2.3 Hz), 8.37 (d, 1H, J=2.2 Hz), 7.75 (m, 3H), 7.36 (s, 1H), 7.14 (d,2H, J=8.7 Hz), 4.72 (m, 1H), 4.14 (m, 1H), 3.96 (s, 3H), 3.90 (m, 1H),3.36 (m, 1H), 3.29 (m, 1H), 2.35 (s, 3H), 2.00 (br m, 3H), 1.55-1.64 (brm, 2H), 0.71 (m, 4H).

Example 443.{4-[4-(7-Methoxy-6-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

This example was synthesized from4-[4-(7-methoxy-6-methylquinolin-3-yl)-phenoxy]-piperidine 2HCl (90 mg,0.2 mmol) and (R)-tetrahydrofuran-2-carboxylic acid (41 uL, 0.43 mmol)in an analogous manner to Example 418. Product isolated as a solid (0.06g, 60%). Analysis: LCMS m/z=447 (M+1). ¹H NMR (DMSO-d6) δ: 9.06 (d, 1H,J=2.3 Hz), 8.37 (d, 1H, J=2.2 Hz), 7.75 (m, 3H), 7.36 (s, 1H), 7.14 (d,2H, J=8.7 Hz), 4.69 (m, 2H), 3.96 (s, 3H), 3.77 (m, 4H), 3.42 (m, 1H),3.29 (m, 1H), 2.35 (s, 3H), 2.01 (br m, 4H), 1.84 (m, 2H), 1.52-1.66 (brm, 2H).

Example 444.1-{4-[4-(6-Fluoro-7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1

4-[4-(6-Fluoro-7-methoxyquinolin-3-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and3-bromo-6-fluoro-7-methoxyquinoline (476 mg, 1.86 mmol) in an analogousmanner to Example 378. Product isolated as a solid (0.5 g, 88%).Analysis: LCMS m/z=453 (M+1).

Step 2

6-Fluoro-7-methoxy-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline wasprepared from the Step 1 product (0.5 g, 1.1 mmol) and TFA (2 mL) in ananalogous manner to Ex. 378. Product isolated as a solid (0.36 g, 93%).Analysis: LCMS m/z=353 (M+1).

Step 3

The title compound was prepared from the Step 2 product above (90 mg,0.2 mmol) and propanoyl chloride (40 uL, 0.4 mmol) in an analogousmanner to Example 396. Product isolated as a solid. Analysis: LCMSm/z=409 (M+1). ¹H NMR (DMSO-d6) δ: 9.13 (d, 1H, J=2.2 Hz), 8.47 (d, 1H,J=2.2 Hz), 7.76 (m, 3H), 7.60 (d, 1H, J=8.4 Hz), 7.14 (m, 2H), 4.71 (m,1H), 4.02 (s, 3H), 3.90 (m, 1H), 3.69 (m, 1H), 3.36 (m, 1H), 3.29 (m,1H), 2.35 (m, 2H), 2.07 (br m, 2H), 1.52-1.64 (br m, 2H), 0.99 (t, 3H,J=7.4 Hz).

Example 445.Cyclopropyl-{4-[4-(6-fluoro-7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

This example was synthesized from6-fluoro-7-methoxy-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline (90 mg,0.2 mmol) and cyclopropanecarbonyl chloride (40 uL, 0.4 mmol) in ananalogous manner to Example 396. Product isolated as a solid (0.06 g,60%). Analysis: LCMS m/z=421 (M+1). ¹H NMR (DMSO-d6) δ: 9.13 (d, 1H,J=2.2 Hz), 8.47 (d, 1H, J=2.2 Hz), 7.76 (m, 3H), 7.60 (d, 1H, J=8.4 Hz),7.14 (m, 2H), 4.73 (m, 1H), 4.02 (s, 3H), 4.00 (m, 1H), 3.88 (m, 1H),3.57 (m, 1H), 3.29 (m, 1H), 2.00 (br m, 3H), 1.54-1.65 (br m, 2H), 0.71(m, 4H).

Example 446.{4-[4-(6-Fluoro-7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

This example was synthesized from6-fluoro-7-methoxy-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline (90 mg,0.2 mmol) and (R)-tetrahydrofuran-2-carboxylic acid (49 uL, 0.51 mmol)in an analogous manner to Example 418. Product isolated as a solid (0.04g, 30%). Analysis: LCMS m/z=451 (M+1). ¹H NMR (DMSO-d₆) δ: 9.13 (d, 1H,J=2.2 Hz), 8.47 (d, 1H, J=2.2 Hz), 7.76 (m, 3H), 7.60 (d, 1H, J=8.4 Hz),7.14 (m, 2H), 4.69 (m, 2H), 4.02 (s, 3H), 3.77 (br m, 4H), 3.43 (m, 1H),3.25 (m, 1H), 2.01 (br m, 4H), 1.84 (m, 2H), 1.51-1.66 (br m, 2H).

Example 447.1-{4-[4-(6-Chloro-7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Step 1

4-[4-(6-Chloro-7-methoxyquinolin-3-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (0.5 g, 1.24 mmol) and3-bromo-6-chloro-7-methoxy-quinoline (338 mg, 1.24 mmol) in an analogousmanner to Example 378. Product isolated as a solid (0.5 g, 86%).Analysis: LCMS m/z=469 (M+1).

Step 2

4-[4-(6-Chloro-7-methoxyquinolin-3-yl)-phenoxy]-piperidine 2HCl wasprepared from the step 1 product above (0.5 g, 1.06 mmol) and TFA (2 mL)in an analogous manner to Example 441 step 2. Product isolated as asolid (0.4 g, 85%). Analysis: LCMS m/z=369 (M+1).

Step 3

The title compound was prepared from the step 2 product above (90 mg,0.2 mmol) and propanoyl chloride (30 uL, 0.4 mmol) in an analogousmanner to Example 396. Product isolated as a solid (0.05 g, 50%).Analysis: LCMS m/z=425 (M+1). ¹H NMR (DMSO-d6) δ: 9.17 (d, 1H, J=2.4Hz), 8.48 (d, 1H, J=2.3 Hz), 8.17 (s, 1H), 7.76 (m, 2H), 7.57 (s, 1H),7.16 (m, 2H), 4.71 (m, 1H), 4.03 (s, 3H), 3.88 (m, 1H), 3.73 (m, 1H),3.35 (m, 1H), 3.29 (m, 1H), 2.33 (m, 2H), 1.98 (br m, 2H), 1.52-1.64 (brm, 2H), 0.99 (t, 3H, J=7.4 Hz).

Example 448.{4-[4-(6-Chloro-7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-cyclopropylmethanone

This example was synthesized from4-[4-(6-chloro-7-methoxy-quinolin-3-yl)-phenoxy]-piperidine 2HCl (90 mg,0.2 mmol) and cyclopropanecarbonyl chloride (30 uL, 0.4 mmol) in ananalogous manner to Example 396. Product isolated as a solid (0.06 g,60%). Analysis: LCMS m/z=437 (M+1). ¹H NMR (DMSO-d6) δ: 9.17 (d, 1H,J=2.4 Hz), 8.48 (d, 1H, J=2.3 Hz), 8.17 (s, 1H), 7.76 (m, 2H), 7.57 (s,1H), 7.16 (m, 2H), 4.73 (m, 1H), 4.03 (s, 3H), 3.89 (m, 2H), 3.56 (m,1H), 3.29 (m, 1H), 2.00 (br m, 3H), 1.55-1.64 (br m, 2H), 0.71 (m, 4H).

Example 449.{4-[4-(6-Chloro-7-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

This example was synthesized from4-[4-(6-chloro-7-methoxyquinolin-3-yl)-phenoxy]-piperidine 2HCl (90 mg,0.2 mmol) and (R)-tetrahydrofuran-2-carboxylic acid (41 uL, 0.43 mmol)in an analogous manner to Example 418. Product isolated as a solid (0.05g, 50%). Analysis: LCMS m/z=467 (M+1). ¹H NMR (DMSO-d6) δ: 9.17 (d, 1H,J=2.4 Hz), 8.48 (d, 1H, J=2.3 Hz), 8.17 (s, 1H), 7.76 (m, 2H), 7.57 (s,1H), 7.16 (m, 2H), 4.73 (m, 2H), 4.03 (s, 3H), 3.87 (m, 4H), 3.36 (m,1H), 3.29 (m, 1H), 2.01 (m, 4H), 1.84 (m, 2H), 1.52-1.66 (br m, 2H).

Example 450.{4-[4-(6-Methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone,HCl

Step 1

4-[4-(6-Methoxyquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and 3-bromo-6-methoxy-quinoline(295 mg, 1.24 mmol) in an analogous manner to Example 378. Productisolated as a solid (0.52 g, 96%). Analysis: LCMS m/z=435 (M+1).

Step 2

4-[4-(6-Methoxyquinolin-3-yl)-phenoxy]-piperidine 2HCl was prepared fromthe Step 1 product above (0.52 g, 1.2 mmol) and TFA (2 mL) in ananalogous manner to Ex. 441 step 2. Product isolated as a solid (0.39 g,80%). Analysis: LCMS m/z=335 (M+1).

Step 3

The title compound was prepared from the Step 2 product above (90 mg,0.2 mmol) and (R)-tetrahydrofuran-2-carboxylic acid (41 uL, 0.43 mmol)in an analogous manner to Example 424. Product isolated as a solid (0.07g, 60%). Analysis: LCMS m/z=433 (M+1). ¹H NMR (DMSO-d6) δ: 9.26 (d, 1H,J=1.8 Hz), 8.86 (s, 1H), 8.08 (d, 1H, J=10.0 Hz), 7.88 (d, 2H, J=8.8Hz), 7.55 (m, 2H), 7.21 (d, 2H, J=8.8 Hz), 4.75 (m, 1H), 4.69 (m, 1H),3.95 (s, 3H), 3.77 (br m, 4H), 3.23-3.48 (br m, 2H), 1.99 (br m, 4H),1.84 (m, 2H), 1.52-1.67 (br m, 2H).

Example 451.{4-[4-(3-Isopropoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Step 1

To 6-bromoisoquinolin-3-ol (0.5 g, 2.23 mmol) in DMF (4 mL) under anitrogen atmosphere was added cesium carbonate (2.18 g, 6.69 mmol),followed by isopropyl iodide (0.22 mL, 2.23 mmol) and the reaction washeated at 80° C. for 2 h. The reaction was cooled at RT, diluted withEtOAc, washed with water several times, washed with brine, dried overNa₂SO₄, and concentrated. The product was purified via silica gelchromatography (5% EtOAc/hexanes) and concentrated.6-Bromo-3-isopropoxyisoquinoline was isolated as a solid (0.2 g, 33%).Analysis: LCMS m/z=267 (M+1).

Step 2

4-[4-(3-Isopropoxy-isoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.25 g, 0.61 mmol) and6-bromo-3-isopropoxy-isoquinoline (195 mg, 0.73 mmol) in an analogousmanner to Example 378. Product isolated as a solid (0.25 g, 89%).Analysis: LCMS m/z=463 (M+1).

Step 3

3-Isopropoxy-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline was preparedfrom the Step 2 product above (0.25 g, 0.54 mmol) and TFA (1 mL) in ananalogous manner to Example 378 step 2. Product isolated as a solid(0.19 g, 98%). Analysis: LCMS m/z=363 (M+1).

Step 4

{4-[4-(3-Isopropoxyisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanonewas prepared from the Step 3 product above (90 mg, 0.2 mmol and(R)-tetrahydrofuran-2-carboxylic acid (27 uL, 0.28 mmol) in an analogousmanner to Example 418. isolated as a solid (0.08 g, 60%). Analysis: LCMSm/z=461 (M+1). ¹H NMR (DMSO-d6) δ: 8.99-9.06 (m, 1H), 8.02-8.09 (m, 1H),7.98-8.02 (m, 1H), 7.68-7.79 (m, 3H), 7.11-7.17 (m, 3H), 5.25-5.34 (m,1H), 4.64-4.78 (m. 2H), 3.69-3.86 (m, 4H), 3.33-3.38 (m, 1H), 3.20-3.29(m, 1H), 1.89-2.13 (m, 4H), 1.75-1.88 (m, 2H), 1.44-1.70 (m, 2H), 1.34(d, 6H, J=6.3 Hz)

Example 452.{4-[4-(1-Morpholin-4-yl-isoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Step 1

To an oven dried flask under an atmosphere of argon was added4-[4-(1-chloro-isoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester (0.2 g, 0.46 mmol), morpholine (0.08 mL, 0.91 mmol),cinnamylpalladium chloride dimer (24 mg, 0.046 mmol),di(1-adamantyl)-2-dimethylaminophenylphosphine (38 mg, 0.09 mmol),sodium t-butoxide (0.13 g, 1.37 mmol), followed by toluene (10 mL) andthe reaction was degassed 3× under an atmosphere of argon and wasstirred at 99° C. overnight. The reaction was cooled at rt, diluted withDCM, filtered through a pad of celite, washed with water/brine, driedover sodium sulfate, and concentrated. The product was purified viasilica gel chromatography (10-30-50% ethyl acetate/hexanes) andconcentrated.4-[4-(1-Morpholin-4-yl-isoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester was isolated as a solid (0.1 g, 43%). Analysis:LCMS m/z=490 (M+1).

Step 2

1-Morpholin-4-yl-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline wasprepared from the Step 1 product above (0.1 g, 0.2 mmol) and TFA (1 mL)in an analogous manner to Example 378. Product isolated as a solid (0.07g, 88%). Analysis: LCMS m/z=390 (M+1).

Step 3

The title compound was prepared from the Step 2 product above (67 mg,0.17 mmol) and (R)-tetrahydrofuran-2-carboxylic acid (18 uL, 0.19 mmol)in an analogous manner to Example 418. Product isolated as a solid (0.06g, 72%). Analysis: LCMS m/z=488 (M+1). ¹H NMR (DMSO-d6) δ: 8.12 (m, 3H),7.89 (m, 1H), 7.78 (d, 2H, J=8.7 Hz), 7.45 (d, 1H, J=5.8 Hz), 7.15 (d,2H, J=8.7 Hz), 4.69 (m, 2H), 3.86 (m, 4H), 3.76 (m, 4H), 3.22-3.45 (brm, 6H), 2.01 (br m, 4H), 1.84 (m, 2H), 1.54-1.65 (br m, 2H).

Example 453.{4-[4-(1-Dimethylaminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahyrofuran-2-ylmethananone, HCl

Step 1

4-[4-(1-Dimethylaminoisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester was prepared from4-[4-(1-chloroisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester (0.2 g, 0.46 mmol) and 2M dimethylamine in THF (0.46 mL,0.91 mmol) in an analogous manner to Example 673a. Product isolated as asolid (0.1 g, 52%). Analysis: LCMS m/z=448 (M+1).

Step 2

Dimethyl-{6-[4-(piperidin-4-yloxy)-phenyl]-isoquinolin-1-yl}-amine wasprepared from the Step 1 product above (0.1 g, 0.24 mmol) and TFA (1 mL)in an analogous manner to Example 599b. Product isolated as a solid(0.06 g, 67%). LCMS m/z=348 (M+1).

Step 3

The title compound was prepared the Step 2 product above (55 mg, 0.16mmol) and (R)-tetrahydrofuran-2-carboxylic acid (17 uL, 0.17 mmol) in ananalogous manner to Example 645. Product isolated as a solid (0.04 g,52%). Analysis: LCMS m/z=446 (M+1). ¹H NMR (DMSO-d6) δ: 12.84 (br s,1H), 8.43 (d, 1H, J=9.0 Hz), 8.28 (s, 1H), 8.02 (m, 1H), 7.87 (d, 2H,J=8.8 Hz), 7.75 (d, 1H, J=6.3 Hz), 7.41 (d, 1H, J=6.6 Hz), 7.19 (d, 2H,J=8.8 Hz), 4.75 (m, 1H), 4.69 (m, 1H), 3.76 (br m, 4H), 3.44 (s, 3H),3.41 (s, 3H), 3.33 (m, 1H), 3.25 (m, 1H), 1.99 (br m, 4H), 1.84 (m, 2H),1.52-1.68 (br m, 2H).

Example 454.{4-[4-(1-Aminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone

This example was synthesized from[(2R)-tetrahydrofuran-2-yl]-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1-piperidyl]methanone(0.1 g, 0.2 mmol) and 6-bromoisoquinolin-1-ylamine (67 mg, 0.3 mmol) inan analogous manner to Example 436. Product isolated as a solid (0.03 g,30%). Analysis: LCMS m/z=418 (M+1). ¹H NMR (DMSO-d6) δ: 8.28 (m, 1H),7.95 (s, 1H), 7.75 (m, 4H), 7.12 (m, 2H), 6.95 (m, 3H), 4.72 (m, 2H),3.80 (m, 4H), 3.36 (m, 1H), 3.29 (m, 1H), 1.99 (br m, 4H), 1.82 (m, 2H),1.60 (br m, 2H).

Example 455.{4-[4-(1-Dimethylaminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone,2HCL

Step 1

4-{4-[1-(4-Methylpiperazin-1-yl)-isoquinolin-6-yl]-phenoxy}-piperidine-1-carboxylicacid t-butyl ester was prepared from4-[4-(1-chloro-isoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester (0.2 g, 0.46 mmol) and 1-methylpiperazine (0.1 mL, 0.91mmol) in an analogous manner to Example 452. Product isolated as a solid(0.08 g, 36%). Analysis: LCMS m/z=503 (M+1).

Step 2

The step 1 product above was dissolved in DCM (4 mL), TFA (1 mL) wasadded dropwise and was stirred at rt for 1 h and concentrated.1-(4-Methylpiperazin-1-yl)-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinolinedi-trifluoroacetate was isolated as the crude product. Analysis: LCMSm/z=403 (M+1).

Step 3

The title compound was prepared from4-{4-[1-(4-methylpiperazin-1-yl)-isoquinolin-6-yl]-phenoxy}-piperidinetri-trifluoroacetate (14 mg, 0.19 mmol) and(R)-tetrahydrofuran-2-carboxylic acid (20 uL, 0.21 mmol) in an analogousmanner to Example 424. Product isolated as a solid (0.04 g, 37%).Analysis: LCMS m/z=501 (M+1). ¹H NMR (DMSO-d6) δ: 11.13 (br s, 1H), 8.26(s, 1H), 8.22 (d, 1H, J=8.8 Hz), 8.09 (d, 1H, J=6.0 Hz), 7.98 (m, 1H),7.83 (d, 2H, J=8.8 Hz), 7.60 (d, 1H, J=6.2 Hz), 7.18 (d, 2H, J=8.8 Hz),4.69 (m, 2H), 3.25-4.04 (br m, 15H), 2.87 (s, 3H), 2.02 (m, 4H), 1.84(m, 2H), 1.52-1.66 (br m, 2H).

Example 456.{4-[4-(1-Methylaminoisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Step 1

4-[4-(1-Methylaminoisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester was prepared from4-[4-(1-chloroisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester (0.09 g, 0.2 mmol) and 2M methylamine in THF (0.2 mL, 0.4mmol) in an analogous manner to Example 452. Product isolated as a solid(0.07 g, 80%). Analysis: LCMS m/z=434 (M+1).

Step 2

Methyl-{6-[4-(piperidin-4-yloxy)-phenyl]-isoquinolin-1-yl}-amine wasprepared from the Step 1 product above (0.07 g, 0. 16 mmol) and TFA (0.5mL) in an analogous manner to Example 379. Product isolated as a solid(0.05 g, 100%). LCMS m/z=334 (M+1).

Step 3

The title compound was prepared from the Step 2 product above (53 mg,0.16 mmol) and (R)-tetrahydrofuran-2-carboxylic acid (15 uL, 0.16 mmol)in an analogous manner to Example 418. Product isolated as a solid (0.02g, 29%). Analysis: LCMS m/z=432 (M+1). ¹H NMR (DMSO-d6) δ: 8.22 (m, 1H),8.92 (m, 2H), 7.75 (m, 3H), 7.45 (m, 1H), 7.12 (m, 2H), 6.90 (m, 1H),4.72 (m, 2H), 3.80 (m, 4H), 3.36 (m, 1H), 3.29 (m, 1H), 2.98 (m, 3H),2.00 (br m, 4H), 1.85 (m, 2H), 1.52-1.64 (br m, 2H).

Example 457.1-{4-[4-(4-Methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-oneHCl

Step 1

4-[4-(4-Methylisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidtert-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (0.5 g, 1.24 mmol) and6-bromo-4-methyl-isoquinoline (0.33 g, 1.49 mmol) in an analogous mannerto Example 378. Product isolated as a solid (0.55 g, 100%). Analysis:LCMS m/z=419 (M+1).

Step 2

4-[4-(4-Methylisoquinolin-6-yl)-phenoxy]-piperidine, 2HCl was preparedfrom the Step 1 product above (0.55 g, 1.32 mmol) and TFA (1 mL) in ananalogous manner to Ex. 662b. Product isolated as a solid (0.39 g, 76%).Analysis: LCMS m/z=319 (M+1).

Step 3

The title compound was prepared from the Step two product above (90 mg,0.2 mmol) and propanoyl chloride (30 uL, 0.4 mmol) in an analogousmanner to Example 619. Product isolated as a solid (0.04 g, 40%).Analysis: LCMS m/z=375 (M+1). ¹H NMR (DMSO-d6) δ: 9.68 (s, 1H),8.50-8.62 (m, 2H), 8.42 (s, 1H), 8.27-8.35 (m, 1H), 7.98 (d, 2H, J=8.8Hz), 7.21 (d, 2H, J=8.8 Hz), 4.66-5.01 (m, 1H), 4.01-4.32 (brm, 1H),3.79-3.96 (m, 1H), 3.60-3.76 (m, 1H), 3.15-3.40 (m, 2H), 2.82 (s, 3H),2.35 (d, 2H, J=7.5 Hz), 1.82-2.13 (m, 2H), 1.45-1.77 (m, 2H), 1.00 (t,3H, J=7.4 Hz).

Example 458

Cyclopropyl-{4-[4-(4-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone,HCl

This example was synthesized from4-[4-(4-methylisoquinolin-6-yl)-phenoxy]-piperidine, 2HCl (90 mg, 0.2mmol) and cyclopropanecarbonyl chloride (40 uL, 0.4 mmol) in ananalogous manner to Example 398. Product isolated as a solid (0.06 g,60%). Analysis: LCMS m/z=387 (M+1). ¹H NMR (DMSO-d₆) δ: 9.67 (s, 1H),8.49-8.60 (m, 2H), 8.42 (s, 1H), 8.25-8.35 (m, 1H), 7.99 (d, 2H, J=8.8Hz), 7.22 (d, 2H, J=8.8 Hz), 4.65-4.99 (m, 1H), 3.43-4.17 (m, 4H),3.18-3.38 (m, 1H), 2.82 (s, 3H), 1.81-2.23 (m, 3H), 1.41-1.79 (m, 2H),0.52-0.92 (m, 4H).

Example 459.{4-[4-(4-Methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone,HCl

This example was synthesized from4-[4-(4-methylisoquinolin-6-yl)-phenoxy]-piperidine, 2HCl (90 mg, 0.2mmol) and (R)-tetrahydrofuran-2-carboxylic acid (0.02 mL, 0.25 mmol) inan analogous manner to Example 424. Product isolated as a solid (0.07 g,62%). Analysis: LCMS m/z=417 (M+1). ¹H NMR (DMSO-d6) δ: 9.65 (s, 1H),8.48-8.59 (m, 2H), 8.40 (s, 1H), 8.32 (m, 1H), 7.98 (d, 2H, J=8.8 Hz),7.21 (d, 2H, J=8.5 Hz), 4.54-4.87 (m, 2H), 3.52-3.92 (m, 5H), 3.20-3.50(m, 2H), 2.82 (s, 3H), 1.93-2.18 (m, 4H), 1.73-1.90 (m, 2H), 1.45-1.66(m, 2H).

Example 460.1-{4-[4-(5-Methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,HCl

Step 1

4-[4-(5-Chloroquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and 3-bromo-5-chloro-quinoline(0.36 g, 1.49 mmol) in an analogous manner to Example 378. Productisolated as a solid. Analysis: LCMS m/z=439 (M+1).

Step 2

4-[4-(5-Methyl-quinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from the Step 1 product above (0.58 g, 1.32mmol) and methylboronic acid (396 mg, 6.62 mmol) in an analogous mannerto Example 430. Product isolated as a solid. Analysis: LCMS m/z=419(M+1).

Step 3

4-[4-(5-Methyl-quinolin-3-yl)-phenoxy]-piperidine 2HCl was prepared fromthe Step 2 product above and TFA (2 mL) in an analogous manner toExample 441 step 2. Product isolated as a solid. LCMS m/z=319 (M+1).

Step 4

The title compound was prepared from the Step 3 product above (90 mg,0.2 mmol) and propanoyl chloride (30 uL, 0.4 mmol) in an analogousmanner to Example 398. Product isolated as a solid (0.05 g, 50%).Analysis: LCMS m/z=375 (M+1). ¹H NMR (DMSO-d6) δ: 9.39 (s, 1H),8.83-8.90 (m, 1H), 8.01 (d, 1H, J=8.8 Hz), 7.93 (d, 2H, J=8.8 Hz),7.74-7.83 (m, 1H), 7.55-7.64 (m, 1H), 7.20 (d, 2H, J=8.8 Hz), 4.70-4.81(m, 1H), 4.40 (br m, 1H), 3.82-3.97 (m, 1H), 3.63-3.79 (m, 1H),3.19-3.47 (m, 2H), 2.80 (s, 3H), 2.28-2.42 (m, 2H), 1.87-2.09 (m, 2H),1.47-1.72 (m, 2H), 1.00 (t, 3H, J=7.4 Hz).

Example 461.Cyclopropyl-{4-[4-(5-methyl-quinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone,HCl

This example was synthesized from4-[4-(5-methylquinolin-3-yl)-phenoxy]-piperidine, 2HCl (90 mg, 0.2 mmol)and cyclopropanecarbonyl chloride (40 uL, 0.4 mmol) in an analogousmanner to Example 398. Product isolated as a solid (0.05 g, 50%).Analysis: LCMS m/z=387 (M+1). ¹H NMR (DMSO-d6) δ: 9.48 (s, 1H),8.93-9.08 (m, 1H), 8.04-8.13 (m, 1H), 7.97 (d, 2H, J=8.5 Hz), 7.79-7.89(m, 1H), 7.50-7.72 (m, 1H), 7.23 (d, 2H, J=8.8 Hz), 4.68-4.88 (m, 1H),3.78-4.09 (m, 2H), 3.53-3.69 (m, 1H), 3.22-3.38 (m, 1H), 2.83 (s, 3H),1.86-2.17 (m, 3H), 1.46-1.77 (m, 2H), 0.73 (d, 4H, J=8.8 Hz).

Example 462.{4-[4-(5-Methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone,HCl

This example was synthesized from4-[4-(5-methylquinolin-3-yl)-phenoxy]-piperidine 2HCl (90 mg, 0.2 mmol)and (R)-tetrahydrofuran-2-carboxylic acid (0.02 mL, 0.25 mmol) in ananalogous manner to Example 424. Product isolated as a solid (0.06 g,53%). Analysis: LCMS m/z=417 (M+1). ¹H NMR (DMSO-d6) δ: 9.45 (d, 1H,J=1.8 Hz), 8.96 (s, 1H), 8.02-8.10 (m, 1H), 7.96 (d, 2H, J=8.8 Hz),7.74-7.86 (m, 1H), 7.58-7.70 (m, 1H), 7.21 (d, 2H, J=8.5 Hz), 4.59-4.84(m, 2H), 3.76 (d, 4H, J=6.8 Hz), 3.17-3.57 (m, 2H), 2.82 (s, 3H),1.91-2.15 (m, 4H), 1.76-1.89 (m, 2H), 1.46-1.71 (m, 2H).

Example 463.1-{4-[4-(5-Methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,HCl

Step 1

4-[4-(5-Methoxyquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and 3-bromo-5-methoxy-quinoline(0.35 g, 1.49 mmol) in an analogous manner to Example 378. Productisolated as a solid. (0.53 g, 100%). Analysis: LCMS m/z=435 (M+1).

Step 2

5-Methoxy-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline 2HCl was preparedfrom the product of Step 1 above (0.53 g, 1.24 mmol) and TFA (2 mL) inan analogous manner to Example 461. Product isolated as a solid (0.48 g,95%). LCMS m/z=335 (M+1).

Step 3

The title compound was prepared from the Step 2 product above (90 mg,0.2 mmol) and propanoyl chloride (30 uL, 0.4 mmol) in an analogousmanner to Example 398. Product isolated as a solid (0.05 g, 50%). LCMSm/z=391 (M+1). ¹H NMR (DMSO) δ: 9.43 (d, 1H, J=2.2 Hz), 8.95 (s, 1H),7.89 (m, 3H), 7.79 (m, 1H), 7.26 (m, 1H), 7.19 (m, 2H), 4.74 (m, 1H),4.07 (s, 3H), 3.88 (m, 1H), 3.69 (m, 1H), 3.25-3.39 (br m, 2H), 2.34 (m,2H), 1.98 (m, 2H), 1.53-1.68 (br m, 2H), 1.00 (t, 3H, J=7.4 Hz).

Example 464.Cyclopropyl-{4-[4-(5-methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

This example was synthesized from5-methoxy-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline, 2HCl (90 mg, 0.2mmol) and cyclopropanecarbonyl chloride (40 uL, 0.4 mmol) in ananalogous manner to Example 619. Product isolated as a solid (0.07 g,70%). Analysis: LCMS m/z=403 (M+1). ¹H NMR (DMSO-d6) δ: 9.44 (d, 1H,J=2.3 Hz), 8.97 (s, 1H), 7.89 (m, 3H), 7.79-7.81 (m, 1H), 7.24-7.29 (m,1H), 7.20 (d, 2H, J=8.8 Hz), 4.60-4.90 (m, 1H), 4.08 (s, 3H), 3.96-4.02(m, 1H), 3.81-3.92 (m, 1H), 3.51-3.70 (m, 1H), 3.20-3.38 (m, 1H), 2.01(m, 3H), 1.45-1.77 (m, 2H), 0.64-0.77 (m, 4H).

Example 465.{4-[4-(5-Methoxyquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone,HCl

This example was synthesized from5-methoxy-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline, 2HCl (90 mg, 0.2mmol) and (R)-tetrahydrofuran-2-carboxylic acid (0.02 mL, 0.24 mmol) inan analogous manner to Example 424. Product isolated as a solid (0.06 g,58%). Analysis: LCMS m/z=433 (M+1). ¹H NMR (DMSO-d₆) δ: 9.44 (d, 1H,J=2.3 Hz), 8.97 (s, 1H), 7.89 (m, 3H), 7.73-7.81 (m, 1H), 7.23-7.32 (m,1H), 7.19 (d, 2H, J=8.8 Hz), 4.62-4.84 (m, 2H), 4.08 (s, 3H), 3.76 (m,4H), 3.08-3.56 (m, 2H), 2.00 (m, 4H), 1.74-1.92 (m, 2H), 1.41-1.70 (m,2H).

Example 466.Cyclopropyl-[4-(4-isoquinolin-6-yl-phenoxy)-piperidin-1-yl]-methanone

Step 1

4-(4-Isoquinolin-6-yl-phenoxy)-piperidine-1-carboxylic acid t-butylester was prepared from 4-(4-iodo-phenoxy)-piperidine-1-carboxylic acidt-butyl ester (0.5 g, 1.24 mmol) and 6-isoquinolylboronic acid (0.26 g,1.49 mmol) in an analogous manner to Example 378. Product was isolatedas a solid (0.33 g, 65%). Analysis: LCMS m/z=405 (M+1).

Step 2

6-[4-(Piperidin-4-yloxy)-phenyl]-isoquinoline was prepared from the Step1 product above (0.33 g, 0.8 mmol) and TFA (2 mL) in an analogous mannerto Example 378. Product isolated as a solid (0.24 g, 97%). Analysis:LCMS m/z=305 (M+1).

Step 3

The title compound was prepared from the Step 2 product above andcyclopropanecarbonyl chloride (40 uL, 0.5 mmol) in an analogous mannerto Example 396. Product isolated as a solid (0.06 g, 50%). Analysis:LCMS m/z=373 (M+1). ¹H NMR (DMSO-d6) δ: 9.31 (s, 1H), 8.50 (d, 1H, J=5.8Hz), 8.19 (m, 2H), 8.01 (d, 1H, J=1.8 Hz), 7.81 (m, 3H), 7.16 (d, 2H,J=8.8 Hz), 4.70-4.83 (m, 1H), 3.83-4.07 (m, 2H), 3.52-3.64 (m, 1H),3.24-3.31 (m, 1H), 1.90-2.09 (m, 3H), 1.49-1.72 (m, 2H), 0.73 (m, 4H).

Example 467.[4-[4-(6-Isoquinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanoneHCl

This example was synthesized from6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (0.09 g, 0.30 mmol) and(R)-tetrahydrofuran-2-carboxylic acid (0.03 mL, 0.33 mmol) in ananalogous manner to Example 424. Product isolated as a solid (0.08 g,59%). Analysis: LCMS m/z=403 (M+1). ¹H NMR (DMSO-d6) δ: 9.78 (s, 1H),8.61-8.68 (m, 1H), 8.47-8.58 (m, 2H), 8.29-8.42 (m, 2H), 7.93 (d, 2H,J=8.8 Hz), 7.09-7.27 (m, 2H), 4.74-4.83 (m, 1H), 4.70 (m, 1H), 3.77 (s,4H), 3.20-3.53 (m, 2H), 1.91-2.13 (m, 4H), 1.76-1.91 (m, 2H), 1.47-1.73(m, 2H).

Example 468.{4-[4-(5-Methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone,HCl

Step 1

To 6-methoxy-5-methyl-isoquinoline (0.14 g, 0.81 mmol) under anatmosphere of nitrogen in DCM (10 mL) at 0° C. was added 1M of BBr₃ inDCM (2.85 mL, 2.85 mmol) and the reaction was warmed to RT overnight.The reaction was poured slowly into sat. sodium bicarbonate (30 mL) at0° C. with vigorous stirring, extracted, washed with water/brine, driedover sodium sulfate, and concentrated. 5-Methyl-isoquinolin-6-ol wasisolated as crude product (0.1 g, 83%). Analysis: LCMS m/z=160 (M+1).

Step 2

To a solution of 5-methylisoquinolin-6-ol (0.13 g, 0.8 mmol) in DMF (3mL) and DIPEA (0.42 mL, 2.39 mmol) was addedN-phenylbis(trifluoromethanesulphonimide) (0.31 g, 0.88 mmol) and wasstirred at RT for 30 min. The reaction was diluted with ethyl acetate,washed with water/brine, and concentrated. The product was purified viasilica gel chromatography (10-30% EtOAc/hexanes) and concentrated.Trifluoromethanesulfonic acid 5-methyl-isoquinolin-6-yl ester wasisolated as a solid (0.14 g, 59%). Analysis: LCMS m/z=292 (M+1).

Step 3

4-[4-(5-Methylisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.16 g, 0.4 mmol) and the Step 2 product above (0.14g, 0.47 mmol) in an analogous manner to Example 378. Product isolated asa solid (0.13 g, 75%). Analysis: LCMS m/z=419 (M+1).

Step 4

5-Methyl-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline was prepared fromthe Step 3 product above (0.14 g, 0.3 mmol) and TFA (0.5 mL) in ananalogous manner to Ex. 378. Product isolated as a solid (0.09 g, 89%).Analysis: LCMS m/z=319 (M+1).

Step 5

The title compound was prepared from the step 4 product above (0.09 g,0.27 mmol) and (R)-tetrahydrofuran-2-carboxylic acid (0.03 mL, 0.3 mmol)in an analogous manner to Example 424. Product isolated as a solid (0.09g, 74%). Analysis: LCMS m/z=417 (M+1). ¹H NMR (DMSO-d6) δ: 9.83 (s, 1H),8.72 (d, 1H, J=6.5 Hz), 8.51 (d, 1H, J=6.8 Hz), 8.38 (d, 1H, J=8.5 Hz),7.87 (d, 1H, J=8.8 Hz), 7.43 (d, 2H, J=8.8 Hz), 7.17 (d, 2H, J=8.5 Hz),4.70 (m, 2H), 3.68-3.97 (m, 4H), 3.20-3.51 (m, 2H), 2.67 (s, 3H), 2.02(br m, 4H), 1.78-1.92 (m, 2H), 1.49-1.73 (m, 2H).

Example 469.1-[4-[4-(1,4-Dimethyl-6-isoquinolyl)phenoxy]-1-piperidyl]propan-1-one,HCl

Step 1

4-[4-(1-Chloro-4-methyl-isoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and6-bromo-1-chloro-4-methylisoquinoline (0.32 g, 1.24 mmol) in ananalogous manner to Example 378. Product isolated as a solid (0.4 g,70%). Analysis: LCMS m/z=453 (M+1).

Step 2

To a schlenck flask under an atmosphere of argon was added the Step 1product above (0.4 g, 0.87 mmol), methylboronic acid (0.26 g, 4.34mmol), DPPF-Pd(II), complex with DCM (1:1) (142 mg, 0.17 mmol),potassium phosphate (0.92 g, 4.34 mmol), followed by 1,4-dioxane (10 mL)and was degassed under an atmosphere of argon for 5 min and was heatedat 99° C. for 2 h. The reaction was cooled, filtered through a pad ofcelite, washed with 1N Na₂CO₃/water/brine, dried over sodium sulfate,and concentrated. The product was purified via silica gel chromatographyusing (20-50% EtOAc/hexanes) and concentrated. T-butyl4-[4-(1,4-dimethyl-6-isoquinolyl)phenoxy]piperidine-1-carboxylate wasdissolved in DCM (7 mL), TFA (2 mL) was added dropwise and the reactionwas stirred at rt for 1 h and concentrated. The reaction was partitionedbetween DCM/1N sodium carbonate, washed with brine, dried over sodiumsulfate, and concentrated. The product was dissolved in DCM, 2M of HClin diethyl ether (0.43 mL, 0.87 mmol) was added and was concentrated.1,4-Dimethyl-6-[4-(4-piperidyloxy)phenyl]isoquinoline dihydrochloridewas isolated as a solid (0.22 g, 62%). LCMS m/z=333 (M+1).

Step 3

1-[4-[4-(1,4-Dimethyl-6-isoquinolyl)phenoxy]-1-piperidyl]propan-1-oneHCl was prepared from1,4-dimethyl-6-[4-(4-piperidyloxy)phenyl]isoquinoline 2HCl (72 mg, 0.18mmol) and propanoyl chloride (30 uL, 0.3 mmol) in an analogous manner toExample 398. Product isolated as a solid (0.04 g, 53%). Analysis: LCMSm/z=389 (M+1). ¹H NMR (DMSO-d₆) δ: 8.60 (d, 1H, J=8.8 Hz), 8.29-8.41 (m,3H), 7.99 (d, 2H, J=8.8 Hz), 7.21 (d, 2H, J=8.8 Hz), 4.71-4.84 (m, 1H),3.83-3.96 (m, 1H), 3.67-3.77 (m, 1H), 3.23-3.64 (br m, 3H), 3.17 (s,3H), 2.78 (s, 3H), 2.35 (m, 2H), 1.86-2.10 (m, 2H), 1.48-1.72 (m, 2H),1.00 (t, 3H, J=7.4 Hz).

Example 470.Cyclopropyl-[4-[4-(1,4-dimethyl-6-isoquinolyl)phenoxy]-1-piperidyl]methanone,HCl

This example was synthesized from1,4-dimethyl-6-[4-(4-piperidyloxy)phenyl]isoquinoline, 2HCl (72 mg, 0.18mmol) and cyclopropanecarbonyl chloride (30 uL, 0.3 mmol) in ananalogous manner to Example 398. Product isolated as a solid (0.04 g,52%). Analysis: LCMS m/z=401 (M+1). ¹H NMR (DMSO-d₆) δ: 8.60 (d, 1H,J=9.0 Hz), 8.29-8.42 (m, 3H), 7.99 (d, 2H, J=8.8 Hz), 7.22 (d, 2H, J=8.8Hz), 4.80 (m, 1H), 3.83-4.10 (m, 2H), 3.24-3.69 (m, 3H), 3.17 (s, 3H),2.78 (s, 3H), 1.88-2.11 (m, 3H), 1.47-1.76 (m, 2H), 0.64-0.76 (m, 4H).

Example 471.[4-[4-(1,4-Dimethyl-6-isoquinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone,HCl

This example was synthesized from1,4-dimethyl-6-[4-(4-piperidyloxy)phenyl]-isoquinoline 2HCl (72 mg, 0.18mmol) and (R)-tetrahydrofuran-2-carboxylic acid (19 uL, 0.2 mmol) in ananalogous manner to Example 424. Product isolated as a solid (0.03 g,36%). LCMS m/z=432 (M+1). ¹H NMR (DMSO) δ: 8.59 (d, 1H, J=8.8 Hz),8.28-8.42 (m, 3H), 7.99 (d, 2H, J=8.8 Hz), 7.21 (d, 2H, J=8.5 Hz), 4.85(m, 1H), 4.64 (m, 1H), 3.70-3.95 (m, 4H), 3.23-3.61 (m, 3H), 3.15 (s,3H), 2.78 (s, 3H), 1.92-2.15 (m, 4H), 1.79-1.91 (m, 2H), 1.50-1.73 (m,2H).

Example 472.1-[4-[4-(1,5-Dimethyl-6-isoquinolyl)phenoxy]-1-piperidyl]propan-1-oneHCl

Step 1

5-Chloro-6-methoxy-1-methylisoquinoline was prepared from1,5-dichloro-6-methoxyisoquinoline (0.5 g, 2.19 mmol) and methylboronicacid (656 mg, 11 mmol) in an analogous manner to Example 425. Productisolated as a solid (0.4 g, 91%). LCMS m/z=208 (M+1).

Step 2

6-Methoxy-1,5-dimethylisoquinoline was prepared from the Step 1 productabove (0.4 g, 1.99 mmol) and methylboronic acid (597 mg, 9.97 mmol) ananalogous manner to Example 430. Product isolated as a solid (0.37 g,100%). Analysis: LCMS m/z=188 (M+1).

Step 3

1,5-Dimethylisoquinolin-6-ol was prepared from6-methoxy-1,5-dimethylisoquinoline (0.4 g, 2.06 mmol) and 1M of BBr₃ inDCM (7.2 mL, 7.2 mmol) an analogous manner to Example 468. Product wasisolated (0.25 g, 69%). Analysis: LCMS m/z=174 (M+1).

Step 4

Trifluoromethanesulfonic acid 1,5-dimethylisoquinolin-6-yl ester wasprepared from 1,5-dimethylisoquinolin-6-ol (0.25 g, 1.42 mmol) andN-phenylbis(trifluoromethanesulphonimide) (0.56 g, 1.56 mmol) ananalogous manner to Example 468. Product was isolated as a solid (0.22g, 50%). Analysis: LCMS m/z=306 (M+1).

Step 5

To a schlenck flask was added4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.25 g, 0.61 mmol), the Step 4 product above (0.22g, 0.71 mmol), tetrakis(triphenylphosphine)palladium(0) (0.07 g, 0.06mmol), 1M of Na₂CO₃ (1.82 mL, 1.82 mmol), followed by 1,4-dioxane (6 mL)and was degassed under Argon for 5 min and was heated at 99° C.overnight. The reaction was cooled, filtered through a pad of celite,washed with 1N Na₂CO₃/water/brine, dried over Na₂SO₄, and concentrated.The product was purified via silica gel chromatography (20-50%EtOAc/hexanes) and concentrated. T-butyl4-[4-(1,5-dimethyl-6-isoquinolyl)phenoxy]piperidine-1-carboxylate wasdissolved in DCM (6 mL), TFA (0.8 mL) was added dropwise and was stirredat rt for 2 h and concentrated. The compound was partitioned betweenDCM/1N Na₂CO₃, washed with water/brine, dried over Na₂SO₄, andconcentrated. The product was dissolved in DCM, 2M of HCl in diethylether (0.3 mL, 0.61 mmol) was added and was concentrated.1,5-Dimethyl-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline was isolatedas a solid (0.22 g, 90%). Analysis: LCMS m/z=333 (M+1).

Step 6

The title compound was prepared from1,5-dimethyl-6-[4-(4-piperidyloxy)phenyl]-isoquinoline 2HCl (74 mg, 0.18mmol) and propanoyl chloride (30 uL, 0.3 mmol) an analogous manner toExample 619. Product isolated as a solid (0.05 g, 64%). Analysis: LCMSm/z=389 (M+1). ¹H NMR (DMSO-d6) δ: 8.53 (d, 1H, J=6.8 Hz), 8.41 (d, 1H,J=8.8 Hz), 8.34 (d, 1H, J=6.3 Hz), 7.83 (d, 1H, J=8.8 Hz), 7.42 (d, 2H,J=8.8 Hz), 7.16 (d, 2H, J=8.5 Hz), 4.73 (m, 1H), 3.86-3.99 (m, 1H), 3.73(m, 1H), 3.22-3.45 (br m, 2H), 3.19 (s, 3H), 2.65 (s, 3H), 2.36 (m, 2H),1.97 (m, 2H), 1.48-1.75 (m, 2H), 1.00 (t, 3H, J=7.4 Hz).

Example 473.Cyclopropyl-[4-[4-(1,5-dimethyl-6-isoquinolyl)phenoxy]-1-piperidyl]methanoneHCl

This example was synthesized from1,5-dimethyl-6-[4-(4-piperidyloxy)phenyl]isoquinoline, 2HCl (74 mg, 0.18mmol) and cyclopropanecarbonyl chloride (30 uL, 0.3 mmol) in ananalogous manner to Example 398. Product isolated as a solid (0.05 g,56%). Analysis: LCMS m/z=401 (M+1). ¹H NMR (DMSO-d₆) δ: 8.55 (d, 1H,J=7.0 Hz), 8.44 (d, 1H, J=8.8 Hz), 8.38 (d, 1H, J=6.8 Hz), 7.86 (d, 1H,J=8.8 Hz), 7.40-7.46 (m, 2H), 7.13-7.20 (m, 2H), 4.68-4.83 (m, 1H),3.81-4.08 (m, 2H), 3.49-3.65 (m, 2H), 3.23-3.36 (m, 1H), 3.20 (s, 3H),2.67 (s, 3H), 1.91-2.14 (m, 3H), 1.50-1.76 (m, 2H), 0.66-0.78 (m, 4H).

Example 474.[4-[4-(1,5-Dimethyl-6-isoquinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone,HCl

This example was synthesized from1,5-dimethyl-6-[4-(4-piperidyloxy)phenyl]-isoquinoline, 2HCl (74 mg,0.18 mmol) and (R)-tetrahydrofuran-2-carboxylic acid (19 uL, 0.2 mmol)in an analogous manner to Example 424. Product isolated as a solid (0.04g, 47%). Analysis: LCMS m/z=432 (M+1). ¹H NMR (DMSO-d₆) δ: 8.54 (d, 1H,J=7.0 Hz), 8.44 (d, 1H, J=8.8 Hz), 8.39 (d, 1H, J=6.8 Hz), 7.86 (d, 1H,J=8.8 Hz), 7.42 (d, 2H, J=8.8 Hz), 7.17 (d, 2H, J=8.5 Hz), 4.70 (m, 2H),3.52-3.96 (br m, 5H), 3.23-3.51 (br m, 2H), 3.21 (s, 3H), 2.66 (s, 3H),1.93-2.11 (m, 4H), 1.76-1.91 (m, 2H), 1.49-1.72 (m, 2H).

Example 475.[4-[4-(8-Cyclopropyl-7-quinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]methanone,HCl

Step 1

t-Butyl 4-[4-(8-chloro-7-quinolyl)phenoxy]piperidine-1-carboxylate wasprepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.25 g, 0.62 mmol) and 7-bromo-8-chloroquinoline(0.17 g, 0.68 mmol) in an analogous manner to Example 378. Productisolated as a solid (0.23 g, 85%). Analysis: LCMS m/z=439 (M+1).

Step 2

To a schlenck flask under an atmosphere of argon was added the Step 1product (0.23 g, 0.53 mmol), cyclopropyl boronic acid (0.23 g, 2.63mmol), amphos (74.5 mg, 0.11 mmol), cesium carbonate (0.86 g, 2.63mmol), followed by 1,4-dioxane (20 mL)/Water (0.670 mL) and was degassedunder an atmosphere of argon for 5 min and was heated at 120° C. for 4 hand cooled at RT. The reaction was filtered through a pad of celite,washed with DCM, washed with water/brine, dried over sodium sulfate, andconcentrated. The product was purified via silica gel chromatographyusing Prep TLC plates (30% EtOAc/hexanes) and concentrated. Tert-butyl4-[4-(8-cyclopropyl-7-quinolyl)phenoxy]piperidine-1-carboxylate wasdissolved in DCM (4 mL), TFA (1 mL) was added and was stirred at rt for2 h and concentrated. The product was washed with 1N Na₂CO₃/brine, driedover sodium sulfate, and concentrated.8-Cyclopropyl-7-[4-(piperidin-4-yloxy)-phenyl]-quinoline was isolated asa yellow oil (0.05 g, 29%). LCMS m/z=345 (M+1).

Step 3

[4-[4-(8-Cyclopropyl-7-quinolyl)phenoxy]-1-piperidyl]-[(2R)-tetrahydrofuran-2-yl]-methanoneHCl was prepared from the Step 2 product above (52 mg, 0.15 mmol) and(R)-tetrahydrofuran-2-carboxylic acid (16 uL, 0.17 mmol) in an analogousmanner to Example 424. Product isolated as a solid (0.04 g, 55%).Analysis: LCMS m/z=444 (M+1). ¹H NMR (DMSO-d₆) δ: 9.23 (s, 1H),8.95-9.12 (br m, 1H), 8.15-8.26 (m, 1H), 7.95-8.06 (m, 1H), 7.78-7.88(m, 1H), 7.57 (d, 2H, J=8.5 Hz), 7.15 (d, 2H, J=8.5 Hz), 4.71 (m, 2H),4.30 (br m, 1H), 3.66-3.97 (m, 4H), 3.18-3.54 (m, 2H), 2.39-2.47 (m,1H), 1.94-2.12 (m, 4H), 1.84 (m, 2H), 1.48-1.73 (m, 2H), 0.88-1.12 (m,2H), 0.23-0.39 (m, 2H).

Example 476.{4-[4-(3-Ethylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone

Step 1

4-[4-(3-Ethyl-isoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from4-[4-(3-chloroisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester (0.67 g, 1.53 mmol) and ethyl boronic acid (0.57 g, 7.65mmol) analogous to Example 430. Product isolated as a solid. Analysis:LCMS m/z=433 (M+1).

Step 2

3-Ethyl-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline was prepared fromthe Step 1 product above and TFA (2 mL) in an analogous manner toExample 378. Product isolated as a solid (0.09 g, 97%). Analysis: LCMSm/z=333 (M+1).

Step 3

{4-[4-(3-Ethylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanonewas prepared from the Step 2 product above (88 mg, 0.26 mmol) and(R)-tetrahydrofuran-2-carboxylic acid (51 uL, 0.53 mmol) in an analogousmanner to Example 418. Product isolated as a solid (0.05 g, 40%).Analysis: LCMS m/z=431 (M+1). ¹H NMR (DMSO-d6) δ: 9.22 (s, 1H), 8.12 (d,2H, J=8.8 Hz), 7.91 (m, 1H), 7.79 (d, 2H, J=8.8 Hz), 7.66 (s, 1H), 7.15(d, 2H, J=8.7 Hz), 4.69 (m, 2H), 3.77 (br m, 4H), 3.36 (m, 1H), 3.25 (m,1H), 2.90 (m, 2H), 2.01 (br m, 4H), 1.84 (m, 2H), 1.52-1.66 (br m, 2H),1.32 (t, 3H, J=7.6 Hz).

Example 477.Cyclopropyl-{4-[4-(7-fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Step 1

4-[4-(7-Fluoroquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and 3-bromo-7-fluoroquinoline(0.28 g, 1.24 mmol) in an analogous manner to Example 378. Productisolated as a solid. Analysis: LCMS m/z=423 (M+1).

Step 2

7-Fluoro-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline was prepared fromthe Step 1 product above and TFA (2 mL) in an analogous manner toExample 378. Product isolated as a solid (0.29 g, 96%). Analysis: LCMSm/z=323 (M+1).

Step 3

The title compound was prepared from the Step 2 product above (95 mg,0.29 mmol) and cyclopropanecarbonyl chloride (40 uL, 0.5 mmol) in ananalogous manner to Example 396. Product isolated as a solid (0.06 g,52%). Analysis: LCMS m/z=391 (M+1). ¹H NMR (DMSO-d₆) δ: 9.25 (s, 1H),8.64 (s, 1H), 8.12 (m, 1H), 7.81 (m, 2H), 7.76 (m, 1H), 7.58 (m, 1H),7.18 (m, 2H), 4.74 (m, 1H), 3.98 (m, 1H), 3.89 (m, 1H), 3.56 (m, 1H),3.29 (m, 1H), 2.00 (br m, 3H), 1.55-1.66 (br m, 2H), 0.74 (m, 4H).

Example 478.1-{4-[4-(7-Fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

This example was synthesized from7-fluoro-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline (95 mg, 0.29 mmol)and propanoyl chloride (40 uL, 0.5 mmol) in an analogous manner toExample 396. Product isolated as a solid (0.02 g, 19%). Analysis: LCMSm/z=379 (M+1). ¹H NMR (DMSO-d₆) δ: 9.25 (s, 1H), 8.64 (s, 1H), 8.12 (m,1H), 7.81 (m, 2H), 7.76 (m, 1H), 7.58 (m, 1H), 7.18 (m, 2H), 4.72 (m,1H), 3.87 (m, 1H), 3.69 (m, 1H), 3.35 (m, 1H), 3.27 (m, 1H), 2.35 (m,2H), 1.98 (br m, 2H), 1.50-1.65 (br m, 2H), 1.00 (t, 3H, J=7.4 Hz).

Example 479.{4-[4-(7-Fluoroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone

This example was synthesized from7-fluoro-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline (95 mg, 0.29 mmol)and (R)-tetrahydrofuran-2-carboxylic acid (60 uL, 0.63 mmol) in ananalogous manner to Example 418. Product isolated as a solid (0.09 g,65%). Analysis: LCMS m/z=421 (M+1). ¹H NMR (DMSO-d₆) δ: 9.25 (s, 1H),8.64 (s, 1H), 8.12 (m, 1H), 7.81 (m, 2H), 7.76 (m, 1H), 7.58 (m, 1H),7.18 (m, 2H), 4.71 (m, 2H), 3.77 (br m, 4H), 3.36 (m, 1H), 3.26 (m, 1H),2.02 (m, 4H), 1.84 (m, 2H), 1.52-1.66 (m, 2H).

Example 480.{4-[4-(3-Cyclopropylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone

Step 1

4-[4-(3-Cyclopropylisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester was prepared from4-[4-(3-chloroisoquinolin-6-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester (0.59 g, 1.35 mmol) and cyclopropyl boronic acid (0.58 g,6.74 mmol) in an analogous manner to Example 430. Product isolated as asolid (0.08 g, 14%). Analysis: LCMS m/z=445 (M+1).

Step 2

3-Cyclopropyl-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline was preparedfrom the Step 1 product above (0.08 g, 0.19 mmol) and TFA (4 mL) in ananalogous manner to Example 378. Product isolated as a solid (0.06 g,95%). Analysis: LCMS m/z=345 (M+1).

Step 3

{4-[4-(3-Cyclopropylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanonewas prepared from the Step 3 product above (61 mg, 0.18 mmol) and(R)-tetrahydrofuran-2-carboxylic acid (34 uL, 0.35 mmol) in an analogousmanner to Example 418. Product isolated as a solid (0.03 g, 41%).Analysis: LCMS m/z=443 (M+1). ¹H NMR (DMSO-d₆) δ: 9.14 (s, 1H), 8.05 (d,2H, J=9.4 Hz), 7.86 (m, 1H), 7.76 (m, 2H), 7.70 (s, 1H), 7.15 (d, 2H,J=8.7 Hz), 4.69 (m, 2H), 3.77 (br m, 4H), 3.36 (m, 1H), 3.29 (m, 1H),2.22 (m, 1H), 2.01 (m, 4H), 1.80 (m, 2H), 1.54-1.65 (br m, 2H), 0.99 (m,4H).

Example 481.Cyclopropyl-{4-[4-(1-methylisoquinolin-6-yl)-phenoxy]-piperidin-1-yl}-methanone

This example was synthesized from1-methyl-6-[4-(piperidin-4-yloxy)-phenyl]-isoquinoline (63 mg, 0.20mmol) and cyclopropanecarbonyl chloride (30 uL, 0.3 mmol) in ananalogous manner to Example 396. Product isolated as a solid (0.05 g,63%). Analysis: LCMS m/z=387 (M+1). ¹H NMR (DMSO-d₆) δ: 8.34 (d, 1H,J=5.8 Hz), 8.25 (d, 1H J=8.7 Hz), 8.18 (m, 1H), 7.98 (m, 1H), 7.81 (d,2H, J=8.7 Hz), 7.70 (d, 1H, J=5.8 Hz), 7.16 (d, 2H, J=8.7 Hz), 4.74 (m,1H), 3.98 (m, 1H), 3.89 (m, 1H), 3.56 (m, 1H), 3.29 (m, 1H), 2.70 (s,3H), 2.00 (br m, 3H), 1.55-1.65 (br m, 2H), 0.71 (m, 4H).

Example 482.{4-[4-(7-Methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone,HCl

This example was synthesized from7-methyl-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline (90 mg, 0.3 mmol)and (R)-tetrahydrofuran-2-carboxylic acid (54 uL, 0.57 mmol) in ananalogous manner to Example 424. Product isolated as a solid (0.06 g,50%). LCMS m/z=417 (M+1). ¹H NMR (DMSO-d₆) δ: 9.28 (s, 1H), 8.71 (s,1H), 7.93 (d, 1H, J=7.9 Hz), 7.86 (m, 2H), 7.67 (d, 1H, J=6.9 Hz), 7.57(m, 1H), 7.19 (d, 2H, J=8.6 Hz), 5.58 (br m, 1H), 4.74 (m, 2H), 3.77 (m,4H), 3.35-3.48 (br m, 2H), 2.76 (s, 3H), 2.02 (br m, 4H), 1.84 (m, 2H),1.52-1.69 (br m, 2H).

Example 483.1-{4-[4-(6-Methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,HCl

Step 1

4-[4-(6-Methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and 3-bromo-6-methyl-quinoline(413 mg, 1.86 mmol) in an analogous manner to Example 378. Productisolated as a solid (0.49 g, 94%). Analysis: LCMS m/z=419 (M+1).

Step 2

6-Methyl-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline was prepared fromthe Step 2 product above (0.49 g, 1.16 mmol) and TFA (2 mL) in ananalogous manner to Example 378. Product isolated as a solid (0.35 g,94%). Analysis: LCMS m/z=319 (M+1).

Step 3

The title compound was prepared from the Step 2 product above (86 mg,0.27 mmol) and propanoyl chloride (40 uL, 0.5 mmol) in an analogousmanner to Example 398. Product isolated as a solid (0.06 g, 54%).Analysis: LCMS m/z=375 (M+1). ¹H NMR (DMSO-d6) δ: 9.38 (s, 1H), 8.94 (s,1H), 8.13 (d, 1H, J=8.6 Hz), 7.96 (s, 1H), 7.90 (m, 2H), 7.80 (m, 1H),7.21 (m, 2H), 4.75 (m, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.25-3.38 (br m,2H), 2.56 (s, 3H), 2.34 (m, 2H), 1.99 (br m, 2H), 1.51-1.67 (br m, 2H),1.00 (t, 3H, J=7.4 Hz).

Example 484.Cyclopropyl-{4-[4-(6-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone,HCl

This example was synthesized from6-methyl-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline (86 mg, 0.27 mmol)and cyclopropanecarbonyl chloride (40 uL, 0.5 mmol) in an analogousmanner to Example 398. Product isolated as a solid (0.06 g, 61%).Analysis: LCMS m/z=387 (M+1). ¹H NMR (DMSO-d₆) δ: 9.38 (s, 1H), 8.94 (s,1H), 8.13 (d, 1H, J=8.6 Hz), 7.96 (s, 1H), 7.90 (m, 2H), 7.80 (m, 1H),7.21 (m, 2H), 4.77 (m, 1H), 3.99 (m, 1H), 3.89 (m, 1H), 3.57 (m, 1H),3.30 (m, 1H), 2.56 (s, 3H), 2.01 (br m, 3H), 1.50-1.66 (br m, 2H), 0.72(m, 4H).

Example 485.{4-[4-(6-Methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone,HCl

This example was synthesized from6-methyl-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline (86 mg, 0.27 mmol)and (R)-tetrahydrofuran-2-carboxylic acid (52 uL, 0.54 mmol) in ananalogous manner to Example 424. Product isolated as a solid (0.05 g,41%). Analysis: LCMS m/z=417 (M+1). ¹H NMR (DMSO-d₆) δ: 9.38 (s, 1H),8.94 (s, 1H), 8.13 (d, 1H, J=8.6 Hz), 7.96 (s, 1H), 7.90 (m, 2H), 7.80(m, 1H), 7.21 (m, 2H), 4.76 (m, 1H), 4.69 (m, 1H), 3.77 (m, 4H),3.23-3.48 (br m, 2H), 2.56 (s, 3H), 1.99 (br m, 4H), 1.84 (br m, 2H),1.54-1.67 (br m, 2H).

Example 486.1-{4-[4-(8-Methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one,HCl

Step 1

4-[4-(8-Methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidt-butyl ester was prepared from4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid t-butyl ester (0.5 g, 1.24 mmol) and 3-bromo-8-methyl-quinoline(413 mg, 1.86 mmol) in an analogous manner to Example 378. Productisolated as a solid (0.49 g, 94%). Analysis: LCMS m/z=419 (M+1).

Step 2

8-Methyl-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline was prepared fromthe Step 1 product above (0.49 g, 1.17 mmol) and TFA (2 mL) in ananalogous manner to Example 378. Product isolated as a solid (0.36 g,98%). Analysis: LCMS m/z=319 (M+1).

Step 3

The title compound was prepared the Step 2 product above (91 mg, 0.28mmol) and propanoyl chloride (40 uL, 0.5 mmol) in an analogous manner toExample 424. Product isolated as a solid (0.07 g, 59%). Analysis: LCMSm/z=375 (M+1). ¹H NMR (DMSO-d₆) δ: 9.46 (s, 1H), 9.14 (s, 1H), 8.17 (d,1H, J=8.4 Hz), 8.05 (s, 1H), 7.92 (d, 2H, J=8.8 Hz), 7.72 (m, 1H), 7.21(d, 2H, J=8.8 Hz), 4.75 (m, 1H), 3.90 (m, 1H), 3.87 (m, 1H), 3.24-3.38(br m, 2H), 2.61 (s, 3H), 2.34 (m, 2H), 1.92 (br m, 2H), 1.50-1.67 (m,2H), 1.00 (t, 3H, J=7.4 Hz).

Example 487Cyclopropyl-{4-[4-(8-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

This example was synthesized from8-methyl-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline (91 mg, 0.28 mmol)and cyclopropanecarbonyl chloride (40 uL, 0.5 mmol) in an analogousmanner to Example 396. Product isolated as a solid (0.03 g, 28%).Analysis: LCMS m/z=387 (M+1). ¹H NMR (DMSO-d₆) δ: 9.17 (d, 1H, J=2.4Hz), 8.51 (d, 1H, J=2.1 Hz), 7.93 (m, 1H), 7.79 (m, 3H), 7.48 (m, 1H),7.15 (m, 2H), 4.74 (m, 1H), 3.98 (m, 1H), 3.89 (m, 1H), 3.36 (m, 2H),2.54 (s, 3H), 2.00 (br m, 3H), 1.55-1.66 (br m, 2H), 0.71 (m, 4H).

Example 488.{4-[4-(8-Methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-(R)-tetrahydro-furan-2-yl-methanone

This example was synthesized from8-methyl-3-[4-(piperidin-4-yloxy)-phenyl]-quinoline (91 mg, 0.28 mmol)and (R)-tetrahydrofuran-2-carboxylic acid (55 uL, 0.57 mmol) in ananalogous manner to Example 418. Product isolated as a solid (0.05 g,45%). Analysis: LCMS m/z=417 (M+1). ¹H NMR (DMSO-d₆) δ: 9.17 (d, 1H,J=2.4 Hz), 8.51 (d, 1H, J=2.1 Hz), 7.93 (m, 1H), 7.79 (m, 3H), 7.48 (m,1H), 7.15 (m, 2H), 4.73 (m, 2H), 3.71-3.87 (br m, 4H), 3.37 (m, 1H),3.25 (m, 1H), 2.54 (s, 3H), 2.01 (br m, 4H), 1.84 (m, 2H), 1.53-1.66 (brm, 2H).

Example 489 4-(3′,4′-Dimethoxybiphenyl-4-yloxy)-piperidine-1-carboxylicacid t-butyl ester

Palladium acetate (0.008 g, 0.04 mmol), triphenylphosphine (0.023 g,0.088 mmol) and 1,4-dioxane (4.6 mL) were combined and stirred.4-(4-Iodophenoxy)-piperidine-1-carboxylic acid t-butyl ester (0.408 g,1.01 mmol), 3,4-dimethoxyphenylboronic acid (0.218 g, 1.20 mmol), DMF(6.7 mL), 1 M of aqueous Na₂CO₃ solution (1.5 mL, 1.5 mmol) was addedand the reaction was purged with nitrogen and heated at 80° C. for 2hours. The reaction was concentrated and the residue was dissolved inEtOAc, washed with 1M Na₂CO₃, water, and brine. The organic phase wasdried over MgSO₄, filtered, concentrated and purified by normal phasechromatography eluting with EtOAc/hexane to yield 220 mg (53%) of anoff-white solid. Analysis: LCMS: m/z=314 (M+1); ¹H NMR (400 MHz, CDCl₃)δ: 7.46 (m, 2H), 7.07 (m, 2H), 6.94 (m, 3H), 4.50 (m, 1H), 3.94 (s, 3H),3.91 (s, 3H), 3.72 (m, 2H), 3.36 (m, 2H), 1.93 (m, 2H), 1.79 (m, 2H),1.48 (s, 9H).

Example 490. 4-(4′-Cyano-biphenyl-4-yloxy)-piperidine-1-carboxylic acidt-butyl ester

This example was prepared using the previous procedure with4-cyanophenyl-boronic acid to yield the title compound, a white solid(60). Analysis: LCMS: m/z=379 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.85(m, 4H), 7.70 (m, 2H), 7.10 (m, 2H), 4.65 (m, 1H), 3.67 (m, 2H), 3.20(m, 2H), 1.94 (m, 2H), 1.54 (m, 2H), 1.41 (s, 9H).

Example 491.1-[4-(3′,4′-Dimethoxy-biphenyl-4-yloxy)-piperidin-1-yl]-propan-1-one

Step 1

4-(3′,4′-Dimethoxybiphenyl-4-yloxy)-piperidine-1-carboxylic acid t-butylester (0.200 g, 0.484 mmol) and 4 M of HCl in 1,4-dioxane (5.0 mL, 20mmol) were stirred at 60° C. for 80 min. The reaction was concentratedand the residue was dissolved in ethyl acetate, washed with 1M Na₂CO₃,water, and brine. The organic phase was dried with magnesium sulfate,filtered, concentrated and purified by normal phase chromatographyeluting with DCM then 60/40/0.4 DCM/methanol/isopropylamine to yield 82mg (54%) of a white solid. Analysis: LCMS: m/z=314 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ: 7.53 (m, 2H), 7.12 (m, 2H), 6.99 (m, 3H), 4.41 (m, 1H),3.83 (s, 3H), 3.77 (s, 3H), 2.94 (m, 2H), 2.57 (m, 2H), 1.91 (m, 2H),1.45 (m, 2H).

Step 2

4-(3′,4′-Dimethoxybiphenyl-4-yloxy)-piperidine (0.032 g, 0.10 mmol) andDIPEA (0.0534 mL, 0.306 mmol) in THF (2 mL) was added propanoyl chloride(18 uL, 0.20 mmol) and stirred at rt for 1 h. The reaction wasconcentrated, dissolved in EtOAc, and washed with 1 M aqueous Na₂CO₃,water, and brine. Organic phase was dried with MgSO₄, filtered andconcentrated. The residue was purified by normal phase chromatographyeluting with hexane/ethyl acetate to yield 21.5 mg (57%) of a yellowsolid. Analysis: LCMS m/z=370 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.55(m, 2H), 7.13 (m, 2H), 7.01 (m, 3H), 4.64 (m, 1H), 3.89 (m, 1H), 3.88(s, 3H), 3.77 (s, 3H), 3.69 (m, 1H), 3.36 (m, 1H), 3.25 (m, 1H), 2.33(m, 2H), 1.93 (m, 2H), 1.56 (m, 2H), 0.99 (m, 3H).

Example 492.1-[4-(3′,4′-Dimethoxybiphenyl-4-yloxy)-piperidin-1-yl]-2-methyl-propan-1-one

This example was synthesized using isobutyryl chloride to yield a yellowsolid (70%). Analysis: LCMS m/z=384 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ:7.55 (m, 2H), 7.13 (m, 2H), 7.01 (m, 3H), 4.65 (m, 1H), 3.86 (m, 1H),3.83 (s, 3H), 3.77 (s, 3H), 3.76 (m, 1H), 3.39 (m, 1H), 3.26 (m, 1H),2.90 (m, 1H), 1.97 (m, 2H), 1.54 (m, 2H), 1.00 (d, 6H, J=6.7 Hz)

The following examples were synthesized using the procedure for Examples541 and 543.

Example 493. 4′-(1-Propionyl-piperidin-4-yloxy)-biphenyl-4-carbonitrile

The product was isolated as a white solid. Analysis: LCMS m/z=335 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ: 7.86 (m, 4H), 7.70 (m, 2H), 7.11 (m, 2H),4.71 (m, 1H), 3.87 (m, 1H), 3.68 (m, 1H), 3.25 (m, 2H), 2.34 (m, 2H),1.91 (m, 2H), 1.55 (m, 2H), 0.99 (m, 3H).

Example 494. 4′-(1-Isobutyrylpiperidin-4-yloxy)-biphenyl-4-carbonitrile

Analysis: LCMS m/z=349 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.86 (m, 4H),7.70 (m, 2H), 7.11 (m, 2H), 4.72 (m, 1H), 3.83 (m, 2H), 3.33 (m, 2H),2.90 (m, 1H), 1.98 (m, 2H), 1.57 (m, 2H), 1.00 (d, 6H, J=6.7 Hz).

Example 495.4′-(1-Cyclopropanecarbonyl-piperidin-4-yloxy)-biphenyl-4-carbonitrile

Analysis: LCMS: m/z=347 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.86 (m,4H), 7.71 (m, 2H), 7.12 (m, 2H), 4.73 (m, 1H), 3.94 (m, 2H), 3.54 (m,1H), 3.27 (m, 1H), 1.96 (m, 3H), 1.58 (m, 2H), 0.71 (m, 4H).

Example 496. 1-[4-(3-Quinolin-3-yl-phenoxy)-piperidin-1-yl]-propan-1-one

This example was synthesized from4-(3-bromophenoxy)-piperidine-1-carboxylic acid t-butyl ester. Analysis:LCMS: m/z=361 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.25 (d, 1H, J=2.3Hz), 8.66 (m, 1H), 8.06 (m, 2H), 7.78 (m, 1H), 7.66 (m, 1H), 7.46 (m,3H), 7.09 (m, 1H), 4.79 (m, 1H), 3.89 (m, 1H), 3.72 (m, 1H), 3.33 (m,2H), 2.34 (m, 2H), 1.99 (m, 2H), 1.59 (m, 2H), 1.00 (m, 3H).

Example 497.Cyclopropyl-[4-(3-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone

Analysis: LCMS: m/z=3732 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.25 (d,1H, J=2.4 Hz), 8.67 (m, 1H), 8.05 (m, 2H), 7.78 (m, 1H), 7.66 (m, 1H),7.48 (m, 3H), 7.10 (m, 1H), 4.82 (m, 1H), 3.99 (m, 2H), 3.57 (m, 1H),3.33 (m, 1H), 2.01 (m, 3H), 1.62 (m, 2H), 0.72 (m, 4H).

Example 498.1-{4-[4-(5,6-Dimethoxypyridin-3-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS: m/z=371 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.93 (d, 1H,J=1.6 Hz), 7.60 (d, 2H, J=8.6 Hz), 7.48 (s, 1H), 7.07 (d, 2H, J=8.6 Hz),4.67 (m, 1H), 3.87 (m, 7H), 3.70 (m, 1H), 3.27 (m, 2H), 2.33 (m, 2H),1.93 (m, 2H), 1.58 (m, 2H), 0.99 (m, 3H).

Example 499.Cyclopropyl-{4-[4-(5,6-dimethoxypyridin-3-yl)-phenoxy]-piperidin-1-yl}-methanone

Analysis: LCMS: m/z=383 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.93 (d, 1H,J=2.0 Hz), 7.61 (d, 2H, J=8.8 Hz), 7.47 (d, 1H, J=2.0 Hz), 7.07 (d, 2H,J=8.8 Hz), 4.69 (m, 1H), 3.97 (m, 1H), 3.88 (m, 7H), 3.56 (m, 1H), 3.28(m, 1H), 1.97 (m, 3H), 1.57 (m, 2H), 0.71 (m, 4H).

Example 500.1-[4-(3′,4′-Dichlorobiphenyl-4-yloxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS: m/z=378 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.88 (d, 1H,J=2.0 Hz), 7.66 (m, 4H), 7.08 (d, 2H, J=8.8 Hz), 4.69 (m, 1H), 3.87 (m,1H), 3.69 (m, 1H), 3.25 (m, 2H), 2.33 (m, 2H), 1.96 (m, 2H), 1.56 (m,2H), 0.99 (m, 3H).

Example 501.Cyclopropyl-[4-(3′,4′-dichlorobiphenyl-4-yloxy)-piperidin-1-yl]-methanone

Analysis: LCMS: m/z=390 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.88 (d, 1H,J=2.0 Hz), 7.66 (m, 4H), 7.09 (d, 2H, J=8.8 Hz), 4.71 (m, 1H), 3.93 (m,2H), 3.56 (m, 1H), 3.25 (m, 1H), 1.97 (m, 3H), 1.58 (m, 2H), 0.71 (m,4H).

Example 502.1-{4-[4-(2,3-Dihydro-1,4-benzodioxin-6-yl)-phenoxy]-piperidin-1-yl}-propan-1-one

Analysis: LCMS: m/z=368 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.49 (d, 2H,J=8.8 Hz), 7.03 (m, 4H), 6.89 (d, 1H, J=8.4 Hz), 4.63 (m, 1H), 4.26 (s,4H), 3.87 (m, 1H), 3.68 (m, 1H), 3.24 (m, 2H), 2.33 (m, 2H), 1.93 (m,2H), 1.55 (m, 2H), 0.99 (m, 3H).

Example 503.Cyclopropyl-{4-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-phenoxy]-piperidin-1-yl})-methanone

Analysis: LCMS: m/z=380 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.50 (d, 2H,J=8.8 Hz), 7.04 (m, 4H), 6.89 (m, 1H), 4.65 (m, 1H), 4.26 (s, 4H), 3.93(m, 2H), 3.54 (m, 1H), 3.26 (m, 1H), 1.96 (m, 3H), 1.57 (m, 2H), 0.71(m, 4H).

Example 504.1-[4-(4′-Benzyloxy-2′-fluoro-biphenyl-4-yloxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS: m/z=434; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.41 (m, 8H), 6.99(m, 4H), 5.16 (s, 2H), 4.65 (m, 1H), 3.87 (m, 1H), 3.69 (m, 1H), 3.30(m, 2H), 2.33 (m, 2H), 1.94 (m, 2H), 1.56 (m, 2H), 0.99 (m, 3H).

Example 505.[4-(4′-Benzyloxy-2′-fluorobiphenyl-4-yloxy)-piperidin-1-yl]-cyclopropyl-methanone

Analysis: LCMS: m/z=446; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.41 (m, 8H), 7.06(d, 2H, J=8.8 Hz), 6.96 (m, 2H), 5.16 (s, 2H), 4.68 (m, 1H), 3.93 (m,2H), 3.54 (m, 1H), 3.27 (m, 1H), 1.97 (m, 3H), 1.58 (m, 2H), 0.71 (m,4H).

Example 506.1-[4-(5′-Benzyloxy-3′-fluorobiphenyl-4-yloxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS: m/z=434; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.63 (m, 2H), 7.48(m, 2H), 7.41 (m, 2H), 7.34 (m, 1H), 7.07 (m, 4H), 6.85 (m, 1H), 5.19(s, 2H), 4.68 (m, 1H), 3.87 (m, 1H), 3.68 (m, 1H), 3.28 (m, 2H), 2.34(m, 2H), 1.93 (m, 2H), 1.56 (m, 2H), 0.99 (m, 3H).

Example 507.[4-(5′-Benzyloxy-3′-fluorobiphenyl-4-yloxy)-piperidin-1-yl]-cyclopropyl-methanone

Analysis: LCMS: m/z=446; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.63 (m, 2H), 7.48(m, 2H), 7.41 (m, 2H), 7.35 (m, 1H), 7.07 (m, 4H), 6.85 (m, 1H), 5.20(s, 2H), 4.70 (m, 1H), 3.93 (m, 2H), 3.55 (m, 1H), 3.28 (m, 1H), 1.97(m, 3H), 1.58 (m, 2H), 0.71 (m, 4H).

Example 508.1-[4-(4′-Phenoxybiphenyl-4-yloxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS: m/z=402; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.75 (m, 2H), 7.62(m, 2H), 7.56 (m, 2H), 7.41 (m, 2H), 7.16 (m, 1H), 7.05 (m, 6H), 4.65(m, 1H), 3.88 (m, 1H), 3.69 (m, 1H), 3.27 (m, 2H), 2.34 (m, 2H), 1.95(m, 2H), 1.56 (m, 2H), 0.99 (m, 3H).

Example 509.Cyclopropyl-[4-(4′-phenoxybiphenyl-4-yloxy)-piperidin-1-yl]-methanone

Analysis: LCMS: m/z=414; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.60 (m, 4H), 7.41(m, 2H), 7.16 (m, 1H), 7.06 (m, 6H), 4.68 (m, 1H), 3.94 (m, 2H), 3.55(m, 1H), 3.27 (m, 1H), 1.97 (m, 3H), 1.58 (m, 2H), 0.71 (m, 4H).

Example 510.1-[4-(3′-Phenoxybiphenyl-4-yloxy)-piperidin-1-yl]-propan-1-one

Analysis: LCMS: m/z=402; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.56 (m, 2H), 7.41(m, 4H), 7.23 (m, 1H), 7.16 (m, 1H), 7.06 (m, 4H), 6.92 (m, 1H), 4.65(m, 1H), 3.87 (m, 1H), 3.69 (m, 1H), 3.27 (m, 2H), 2.33 (m, 2H), 1.95(m, 2H), 1.56 (m, 2H), 0.99 (m, 3H).

Example 511.Cyclopropyl-[4-(3′-phenoxybiphenyl-4-yloxy)-piperidin-1-yl]-methanone

Analysis: LCMS: m/z=414; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.57 (m, 2H), 7.42(m, 4H), 7.23 (m, 1H), 7.16 (m, 1H), 7.06 (m, 4H), 6.93 (m, 1H), 4.68(m, 1H), 3.93 (m, 2H), 3.54 (m, 1H), 3.27 (m, 1H), 1.96 (m, 3H), 1.58(m, 2H), 0.71 (m, 4H).

Example 512.2-Methyl-1-[4-(4-quinolin-7-yl-benzenesulfonyl)-piperidin-1-yl]-propan-1-one

Step 1.1-[4-(4-Bromobenzenesulfonyl)-piperidin-1-yl]-2-methyl-propan-1-one

4-(4-Bromobenzenesulfonyl)piperidine HCl (0.300 g, 0.881 mmol) suspendedin THF (5 mL) was added DIPEA (0.767 mL, 4.40 mmol) at rt. Isobutyrylchloride (0.186 mL, 1.76 mmol) was added dropwise and the mixturestirred 4 h and concentrated. The residue was partitioned between EtOAcand 1N Na₂CO₃, washed with water and brine the n dried. The product wastriturated with ether to give a white solid (275 mg, 85%). LCMS m/z=375(M+1); ¹H NMR (CDCl₃) δ: 7.70 (s, 4H), 4.76 (m, 1H), 4.09 (m, 1H),2.98-3.14 (m, 2H), 2.69-2.77 (m, 1H), 2.48 (m, 1H), 2.11 (m, 1H), 1.95(m, 1H), 1.60-1.72 (m, 2H), 1.10 (d, 6H, J=7 Hz).

Step 2.2-Methyl-1-[4-(4-quinolin-7-yl-benzenesulfonyl)-piperidin-1-yl]-propan-1-one

Palladium acetate (0.00195 g, 0.00868 mmol) and triphenylphosphine(0.00911 g, 0.0347 mmol) in 1,4-dioxane (2 mL, 20 mmol) were stirredunder an atmosphere of nitrogen for 15 min.1-[4-(4-Bromobenzenesulfonyl)-piperidin-1-yl]-2-methyl-propan-1-one(0.0650 g, 0.174 mmol), quinoline-7-boronic acid (0.0360 g, 0.208 mmol),DMF (4 mL) and 1 M of sodium carbonate (0.695 mL) were added and heatedat 80° C. for 16 h. The mixture was concentrated, dissolved in EtOAc andwashed with 1N Na₂CO₃, water and brine then dried over MgSO₄. Theproduct was purified on ISCO (95/5 DCM/MeOH). The HCl salt wassynthesized by adding 1N HCl-ether to an EtOAC solution of the base, andcrystallizing the white solid from acetone-ether. Analysis: LCMS m/z=423(M+1); ¹H NMR (DMSO) δ: 9.14 (d, 1H, J=3 Hz), 8.77 (d, 1H, J=8 Hz), 8.50(s, 1H), 8.30 (d, 1H, J=8.7 Hz), 8.16-8.20 (m, 3H), 8.02 (d, 2H, J=8.6Hz), 7.81 (dd, 1H, J=4, 8 Hz), 4.49 (d, 1H, J=12 Hz), 4.05 (d, 1H, J=12Hz), 3.63-3.69 (m, 1H), 3.03 (t, 1H, J=12 Hz), 2.84 (q, 1H, J=7.6 Hz),1.92 (bm, 2H), 1.47 (m, 1H), 1.35 (m, 1H), 0.96 (d, 6H, J=7 Hz). Thefollowing examples were synthesized using1-[4-(4-bromobenzenesulfonyl)piperidin-1-yl]-2-methyl-propan-1-one andthe appropriate boronic acid by the previous procedure.

Example 513.1-[4-(4-Isoquinolin-7-yl-benzenesulfonyl)-piperidin-1-yl]-2-methylpropan-1-one

Analysis: LCMS m/z=423 (M+1); ¹H NMR (CDCl₃) δ: 9.36 (s, 1H), 8.60 (d,1H, J=6 Hz), 8.27 (s, 1H), 8.00 (d, 2H, J=8.5 Hz), 7.97 (s, 2H), 7.91(d, 2H, J=8.5 Hz), 7.71 (d, 1H, J=6 Hz), 4.78 (d, 1H, J=10 Hz), 4.09 (d,1H, J=10 Hz), 3.18 (tt, 1H, J=4, 12 Hz), 3.04 (t, 1H, J=12 Hz), 2.76 (q,1H, J=6 Hz), 2.51 (t, 1H, J=12 Hz), 2.20 (d, 1H, J=12 Hz), 2.02 (d, 1H,J=12 Hz), 1.67-1.73 (m, 3H), 1.10 (d, 6H, J=8 Hz).

Example 514.1-[4-(4-Isoquinolin-6-yl-benzenesulfonyl)-piperidin-1-yl]-2-methyl-propan-1-one

Analysis: LCMS m/z=423 (M+1); ¹H NMR (DMSO-d₆) δ: 9.22 (s, 1H), 8.60 (d,1H, J=6 Hz), 8.12 (d, 1H, J=8.3 Hz), 8.05 (s, 1H), 8.00 (d, 2H, J=8.3Hz), 7.91 (d, 2H, J=8.3 Hz), 7.86 (dd, 1H, J=2, 8 Hz), 7.74 (d, 1H, J=6Hz), 4.78 (d, 1H, J=12 Hz), 4.10 (d, 1H, J=12 Hz), 3.19 (tt, 1H, J=4, 12Hz), 3.04 (t, 1H, J=12 Hz), 2.76 (q, 1H, J=7 Hz), 2.51 (t, 1H, J=12.5Hz), 2.21 (d, 1H, J=10.4 Hz), 2.01 (d, 1H, J=12 Hz), 1.68-1.78 (m, 2H),1.10 (d, 6H, J=7 Hz).

Example 5151-[4-(4-Benzofuran-5-yl-benzenesulfonyl)-piperidin-1-yl]-2-methyl-propan-1-one

Analysis: LCMS m/z=412 (M+1); ¹H NMR (CDCl₃) δ: 7.92 (d, 2H, J=8 Hz),7.83 (d, 1H, J=2 Hz), 7.81 (d, 2H, J=8 Hz), 7.70 (d, 1 h, J=2 Hz), 7.61(d, 1H, J=8.6 Hz), 7.54 (dd, 1H, J=2, 8 Hz), 6.86 (d, 1H, J=2 Hz), 4.78(d, 1H, J=11 Hz), 4.08 (d, 1H, J=11 Hz), 3.16 (tt, 1H, J=4, 12 Hz), 3.03(t, 1H, J=12 Hz), 2.76 (q, 1H, J=7 Hz), 2.51 (t, 1H, J=12 Hz, 2.18 (d,1H, J=11 Hz), 2.00 (d, 1H, J=12 Hz), 1.61-1.73 (m, 2H), 1.10 (d, 6H, J=7Hz).

Example 516.1-(4-((4-(quinolin-7-yl)phenyl)thio)piperidin-1-yl)propan-1-one, HCl

Step 1. 1-(4-((4-Bromophenyl)thio)piperidin-1-yl)propan-1-one

To a solution of 4-((4-bromophenyl)thio)piperidine (500 mg, 1.83 mmol)in DCM (10 mL) was added TEA (0.8 mL, 5.5 mmol) at RT and the reactionmixture was cooled to 0° C. when propionyl chloride (254 mg, 2.75 mol)was added dropwise. The reaction was then stirred at rt for 15 h. Oncompletion, the reaction was diluted with DCM and washed with water. Theorganic layer was dried over Na₂SO₄, concentrated and the crude productwas purified by column chromatography using silica gel to afford1-(4-((4-bromophenyl)thio)piperidin-1-yl)propan-1-one (600 mg, 90%) as acolorless oil. Analysis: ¹H NMR (400 MHz, CD₃OD) δ: 7.49 (m, 2H), 7.35(m, 2H), 4.30 (m, 1H), 3.91 (m, 1H), 3.42 (m, 1H), 3.23 (m, 1H), 2.95(m, 1H), 2.39 (q, J=7.5 Hz, 2H), 1.99 (m, 2H), 1.48 (m, 2H), 1.10 (t,J=7.5 Hz, 3H).

Step 2. 1-(4-((4-(Quinolin-7-yl)phenyl)thio)piperidin-1-yl)propan-1-one,HCl

To a solution of the Step 1 product (1 equiv) in 1,4 dioxane: water(3:1) was added Na₂CO₃ (3 equiv) and quinolin-7-boronic acid (1.2 equiv)and the reaction mixture was degassed with argon for 20 min. This wasfollowed by addition of tetrakis(triphenylphosphine)palladium (0.01equiv) and the reaction mixture was heated at 100° C. for 15 h. Thereaction mixture was cooled to rt and filtered through celite, thefiltrate concentrated, diluted with EtOAc and washed with water. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by column chromatography using silica gel toobtain the free base which was converted to the hydrochloride salt bytreatment with 4M HCl in dioxane to afford1-(4-((4-(quinolin-7-yl)phenyl)thio)piperidin-1-yl)propan-1-onehydrochloride (32%). mp 188° C.; Analysis: LCMS (ESI) 377 (M+1); ¹H NMR(400 MHz, DMSO-d₆) δ: 9.29 (d, J=5.2 Hz, 1H), 9.13 (d, J=8.3 Hz, 1H),8.61 (s, 1H), 8.43 (d, J=8.7 Hz, 1H), 8.29 (d, J=8.7 Hz, 1H), 8.03 (dd,J=8.3, 5.2 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H), 4.21(d, J=13.3 Hz, 1H), 3.81 (d, J=13.3 Hz, 1H), 3.68 (m, 1H), 3.19 (m, 1H),2.88 (m, 1H), 2.31 (t, J=7.4 Hz, 2H), 1.99 (m, 2H), 1.56-1.29 (m, 2H),0.97 (t, J=7.4 Hz, 3H).

The following examples were prepared by analogy to Example 516, usingrequisite heteroaryl boronic acid and acid chloride.

Example 517.1-(4-((4-(Isoquinolin-6-yl)phenyl)thio)piperidin-1-yl)propan-1-one, HCl

Analysis: mp 222° C.; ¹H NMR (400 MHz, DMSO-d₆) δ: 9.89 (s, 1H),8.74-8.58 (m, 3H), 8.49 (d, J=6.6 Hz, 1H), 8.40 (d, J=8.7, 1H), 7.95 (d,J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 4.21 (m, 1H), 3.82 (m, 1H), 3.71(m, 1H), 3.20 (m, 1H), 2.89 (m, 1H), 2.31 (q, J=7.4 Hz, 2H), 1.99 (m,2H), 1.47 (m, 1H), 1.38 (m, 1H), 0.97 (t, J=7.4 Hz, 3H).

Example 518.1-(4-((4-(Quinolin-3-yl)phenyl)thio)piperidin-1-yl)propan-1-one, HCl

Analysis: mp 70° C.; ¹H NMR (400 MHz, CD₃OD) δ: 9.15 (s, 1H), 8.60 (s,1H), 8.11-8.00 (m, 2H), 7.85-7.75 (m, 2H), 7.71-7.51 (m, 4H), 4.32 (m,1H), 3.93 (m, 1H), 3.55 (m, 1H), 3.00 (m, 1H), 2.41 (q, J=7.5 Hz, 2H),2.07 (m, 1H), 1.64-1.54 (m, 1H), 1.56-1.47 (m, 1H), 1.34-1.20 (m, 2H),1.11 (t, J=7.5 Hz, 3H).

Example 519.1-(4-((4-(Isoquinolin-4-yl)phenyl)thio)piperidin-1-yl)propan-1-one, HCl

Analysis: mp 88° C.; ¹H NMR (400 MHz, DMSO-d₆) δ: 9.95 (s, 1H),8.70-8.62 (m, 2H), 8.21 (m, 1H), 8.12-8.01 (m, 2H), 7.62 (m, 4H), 4.22(m, 1H), 3.82 (m, 1H), 3.72 (m, 1H), 3.21 (m, 1H), 2.92 (m, 1H), 2.32(q, J=7.4 Hz, 2H), 2.07-1.96 (m, 2H), 1.58-1.32 (m, 2H), 0.98 (t, J=7.4Hz, 3H).

Example 520.1-(4-((4-(Isoquinolin-6-yl)phenyl)thio)piperidin-1-yl)propan-1-one, HCl

Analysis: mp 120° C.; LCMS (ESI): 391 (M+H)+; ¹H NMR (400 MHz, DMSO-d₆)δ: 9.23 (d, J=5.0 Hz, 1H), 9.00 (d, J=8.3 Hz, 1H), 8.53 (s, 1H), 8.37(d, J=8.7 Hz, 1H), 8.23 (d, J=8.7 Hz, 1H), 7.94 (dd, J=8.3, 5.0 Hz, 1H),7.86 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 4.22 (d, J=13.5 Hz, 1H),3.80 (d, J=13.5 Hz, 1H), 3.68 (m, 1H), 3.23 (m, 1H), 2.87 (m, 2H), 2.00(m, 2H), 1.47 (m, 1H), 1.36 (m, 1H), 0.98 (d, J=6.0 Hz, 6H).

Example 521.1-(4-((4-(Isoquinolin-6-yl)phenyl)thio)piperidin-1-yl)-2-methylpropan-1-oneHCl

Analysis: mp 228° C.; LCMS (ESI): 391 (M+H)+; ¹H NMR (400 MHz, DMSO-d₆)δ: 9.82 (s, 1H), 8.70-8.52 (m, 3H), 8.40 (d, J=6.0 Hz, 1H), 8.34 (d,J=8.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), 4.26-4.17(m, 1H), 3.91 (m, 1H), 3.70 (m, 1H), 3.24 (m, 1H), 2.86 (m, 2H),2.07-1.93 (m, 2H), 1.51-1.33 (m, 2H), 0.98 (d, J=6.7 Hz, 6H).

Example 522.2-Methyl-1-(4-((4-(quinolin-3-yl)phenyl)thio)piperidin-1-yl)propan-1-one,HCl

Analysis: mp 130° C.; LCMS (ESI): 391 (M+H)+; ¹H NMR (400 MHz, DMSO-d₆)δ: 9.48 (s, 1H), 9.09 (s, 1H), 8.22 (d, J=8.6 Hz, 2H), 7.96 (d, J=8.6Hz, 2H), 7.82 (t, J=7.6 Hz, 1H), 7.67-7.50 (m, 3H), 4.22 (m, 1H), 3.91(m, 1H), 3.69 (m, 1H), 3.23 (m, 1H), 2.87 (m, 2H), 2.06-1.92 (m, 2H),1.45-1.31 (m, 2H), 0.98 (d, J=6.5 Hz, 6H).

Example 523.1-(4-((4-(Isoquinolin-4-yl)phenyl)thio)piperidin-1-yl)-2-methylpropan-1-oneHCl

Analysis: mp 120° C.; LCMS (ESI): 391 (M+H)+; ¹H NMR (400 MHz, DMSO-d₆)δ: 9.80 (s, 1H), 8.64 (s, 1H), 8.55 (d, J=8.2 Hz, 1H), 8.12 (m, 1H),8.07-7.96 (m, 2H), 7.67-7.50 (m, 4H), 4.24 (m, 1H), 3.92 (m, 1H), 3.71(m, 1H), 3.25 (m, 1H), 2.88 (m, 2H), 2.03 (m, 2H), 1.49 (m, 1H), 1.39(m, 1H), 0.99 (d, J=7.0 Hz, 6H).

Example 524.1-{4-[Methyl-(4-quinolin-3-yl-phenyl)-amino]-piperidin-1-yl}-propan-1-one,HCl

Step 1. 4-[(4-Bromophenyl)-methyl-amino]-piperidine-1-carboxylic acidtert-butyl ester

A mixture of 4-(4-bromophenylamino)-piperidine-1-carboxylic acid t-butylester (1.5 g, 4.22 mmol), K₂CO₃ (2.91 g, 21.1 mmol), methyl iodide (788μL, 12.6 mmol), and acetonitrile (30 mL) was heated at 80° C. for 24 h.After cooled to RT, the reaction mixture was concentrated. The residuewas diluted with DCM (100 mL), washed with H₂O, brine, dried (Na₂SO₄),and concentrated. The residue was purified by chromatography on silicagel (0-10% MeOH/DCM) gave 1.0 g (64%) of colorless oil. Analysis: ¹H NMR(400 MHz, DMSO-d₆) δ: 7.25-7.31 (2H, m), 6.74-6.80 (2H, m), 3.97-4.10(2H, m), 3.73-3.85 (1H, m), 2.74-2.92 (2H, m), 2.66 (3H, s), 1.48-1.63(4H, m), 1.40 (9H, s).

Step 2 4-[Methyl-(4-quinolin-3-yl-phenyl)-amino]-piperidine-1-carboxylicacid t-butyl ester

A flask charged with4-[(4-bromophenyl)-methylamino]-piperidine-1-carboxylic acid t-butylester (1.0 g, 2.71 mmol), 3-quinolineboronic acid (482 mg, 2.79 mmol),palladium acetate (61 mg, 0.271 mmol), triphenylphosphine (142 mg, 0.542mmol), 1.0 M of Na₂CO₃ (13.5 mL, 13.5 mmol), 1,4-dioxane (10 mL), andDMF (10 mL) was flashed with nitrogen for 15 min. The reaction mixturewas heated at 85° C. for 4 h then RT over 2 days. The reaction mixturewas concentrated and the residue was diluted with EtOAc (100 mL), washedwith 1M Na₂CO₃ solution (35 mL), the water layer was back extracted withEtOAc (50 mL). The combined organic layers were washed with H₂O, brine,dried (Na₂SO₄), and concentrated. The residue was chromatography onsilica gel (0-70% EtOAc/Hexanes) afforded 586 mg (52%) of light brownishoil. Analysis: ¹H NMR (400 MHz, DMSO-d₆) δ: 9.21-9.23 (1H, m), 8.48-8.50(1H, m), 7.98-8.02 (2H, m), 7.72-7.76 (2H, m), 7.67-7.72 (1H, m),7.57-7.63 (1H, m), 6.96-7.01 (2H, m), 4.01-4.12 (2H, m), 3.90-4.00 (1H,m), 2.82-2.97 (2H, m), 2.78 (3H, s), 1.53-1.70 (4H, m), 1.42 (9H, s)ppm.

Step 3. Methylpiperidin-4-yl-(4-quinolin-3-yl-phenyl)-amine

To a solution of4-[methyl-(4-quinolin-3-yl-phenyl)-amino]-piperidine-1-carboxylic acidt-butyl ester (586 mg, 1.40 mmol) in DCM (20 mL) was added 4.0 M of HClin 1,4-dioxane (3.51 mL, 14.0 mmol) dropwise. After 18 h, the red solidprecipitation was collected by filtration, washed with DCM, dried togive 630 mg (100%) of the HCl salt. Analysis: ¹H NMR (400 MHz, DMSO-d₆)δ: 9.58-9.61 (1H, m), 9.28-9.32 (1H, m), 8.99-9.22 (2H, m), 8.36-8.42(1H, m), 8.28-8.33 (1H, m), 8.00-8.06 (1H, m), 7.87-7.96 (3H, m),7.12-7.17 (1H, m), 4.13-4.25 (1H, m), 3.32-3.41 (2H, m), 3.00-3.14 (2H,m), 2.87 (3H, s), 2.00-2.15 (2H, m), 1.76-1.87 (2H, m).

Step 4

A vial charged with methyl-piperidin-4-yl-(4-quinolin-3-yl-phenyl)-amine3HCl (110 mg, 0.26 mmol), DIPEA (449 μL, 2.58 mmol) in DCM (7 mL) wasadded propanoyl chloride (25 μL, 0.28 mmol). After 30 min, the reactionwas quenched with MeOH (3 mL) and concentrated. The residue was purifiedby prep-HPLC and the isolated fractions were combined, neutralized withsaturated NaHCO₃ solution (25 mL), extracted with DCM (3×25 mL). Thecombined organic layers were dried (Na₂SO₄), and concentrated. Theproduct was dissolved in DCM (˜5 mL) and mixed with 1.2 equivalents of0.5 M HCl in MeOH and concentrated. The residue was dissolved in a smallamount of DCM and concentrated—this procedure was repeated severaltimes, collected and dried to give 91 mg (86%) of red solid. Analysis:LCMS m/z 374 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.55-9.61 (1H, m),9.24-9.30 (1H, m), 8.26-8.39 (2H, m), 7.93-8.08 (3H, m), 7.86-7.93 (1H,m), 7.16-7.49 (1H, m), 4.49-4.60 (2H, m), 3.92-4.10 (2H, m), 3.06-3.19(1H, m), 2.85-3.00 (3H, m), 2.55-2.70 (1H, m), 2.34 (2H, q, J=7.5 Hz),1.47-1.85 (4H, m), 1.00 (3H, t, J=7.4 Hz).

The following compounds were synthesized using the procedure for Example524.

Example 525.Cyclopropyl-{4-[methyl-(4-quinolin-3-yl-phenyl)-amino]-piperidin-1-yl}-methanone,HCl

The product was isolated as a red solid. Analysis: LCMS m/z 386 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ: 9.57-9.61 (1H, m), 9.26-9.31 (1H, m),8.34-8.39 (1H, m), 8.27-8.33 (1H, m), 7.94-8.07 (3H, m), 7.86-7.93 (1H,m), 6.90-7.75 (2H, m), 4.47-4.58 (1H, m), 4.34-4.45 (1H, m), 4.01-4.13(1H, m), 3.12-3.28 (1H, m), 2.83-3.04 (3H, m), 2.54-2.74 (1H, m),1.96-2.05 (1H, m), 1.65-1.91 (3H, m), 1.51-1.65 (1H, m), 0.64-0.81 (4H,m).

Example 526.1-[4-(4-Quinolin-3-yl-phenylamino)-piperidin-1-yl]-propan-1-one, HCl

The product was isolated as a dark-red solid. Analysis: LCMS m/z 360(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.52-9.57 (1H, m), 9.18-9.24 (1H,m), 8.24-8.35 (2H, m), 7.96-8.04 (1H, m), 7.82-7.91 (3H, m), 6.94-7.06(2H, m), 4.27-4.37 (1H, m), 3.82-3.92 (1H, m), 3.59-3.71 (1H, m),3.11-3.22 (1H, m), 2.74-2.86 (1H, m), 2.34 (2H, q, J=7.3 Hz), 1.89-2.04(2H, m), 1.25-1.47 (2H, m), 1.00 (3H, t, J=7.4 Hz).

Example 527.Cyclopropyl-[4-(4-quinolin-3-yl-phenylamino)-piperidin-1-yl]-methanone,HCl

The product was isolated as a dark-red solid. Analysis: LCMS m/z 372(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.49-9.53 (1H, m), 9.13-9.19 (1H,m), 8.22-8.32 (2H, m), 7.94-8.01 (1H, m), 7.80-7.90 (3H, m), 6.91-7.02(2H, m), 4.19-4.34 (2H, m), 3.62-3.73 (1H, m), 3.22-3.37 (1H, m),2.77-2.92 (1H, m), 1.88-2.09 (3H, m), 1.25-1.51 (2H, m), 0.68-0.76 (4H,m).

Example 528.{4-[Methyl-(4-quinolin-3-yl-phenyl)-amino]-piperidin-1-yl}-(R)-tetrahydrofuran-2-yl-methanone,HCl

A mixture of methylpiperidin-4-yl-(4-quinolin-3-yl-phenyl)-amine; 3HCl(110 mg, 0.26 mmol), (R)-tetrahydrofuran-2-carboxylic acid (27 μL, 0.28mmol), HATU (117 mg, 0.31 mmol), DIPEA (449 μL, 2.58 mmol) in DCM (5 mL)was stirred at RT for 1 h. The solvent was removed and the residue waspurified by pre-HPLC. The isolated fractions were combined, neutralizedwith sat. NaHCO₃ solution (25 mL), extracted with DCM (3×25 mL). Thecombined organic layers were dried (Na₂SO₄), and concentrated. Theproduct was dissolved in DCM (˜5 mL) and mixed with 1.2 equivalent of0.5 M HCl in MeOH and concentrated. The residue was dissolved in a smallamount of DCM and concentrated—repeated this procedure several times,dried to give 108 mg (93%) of red solid. Analysis: LCMS m/z 416 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ: 9.55-9.61 (1H, m), 9.23-9.29 (1H, m),8.25-8.38 (2H, m), 7.93-8.06 (3H, m), 7.85-7.92 (1H, m), 6.88-7.71 (2H,m), 4.65-4.71 (1H, m), 4.46-4.51 (1H, m), 4.02-4.17 (2H, m), 3.69-3.85(2H, m), 3.06-3.24 (1H, m), 2.81-3.00 (3H, m), 2.61-2.76 (1H, m),1.92-2.15 (2H, m), 1.48-1.91 (6H, m).

Example 529.N-Ethyl-4-[4-(2-hydroxy-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide

Step 1. tert-Butyl4-[4-(2-methoxy-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate

Palladium acetate (0.028 g, 0.124 mmol) and triphenylphosphine (0.13 g,0.50 mmol) in dioxane (10 mL) were stirred 15 min under an atmosphere ofnitrogen.4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (1.00 g, 2.5 mmol),7-bromo-8-methyl-2-methoxyquinoline (0.688 g, 2.73 mmol), DMF (10 mL)and 1 M Na₂CO₃ (7 mL) were added and heated at 90° C. for 18 h. Themixture was concentrated, dissolved in EtOAc, washed with 1N Na₂CO₃,water and brine, then dried (MgSO₄). The product was purified by ISCO(silica get, 80 g column; 20-80% EtOAc/hexanes) to give a white solid(0.8 g, 72%). Analysis: LCMS m/z=449 (M+1). ¹H NMR (CDCl₃) δ 7.98 (d,J=8.8 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.35-7.31 (m, 2H), 7.28 (d, J=8.3Hz, 1H), 7.04-6.95 (m, 2H), 6.90 (d, J=8.8 Hz, 1H), 4.54 (dquin, J=7.1,3.3 Hz, 1H), 4.09 (s, 3H), 3.83-3.67 (m, 2H), 3.45-3.29 (m, 2H), 2.65(s, 3H), 2.04-1.93 (m, 2H), 1.89-1.75 (m, 2H), 1.48 (s, 9H).

Step 2. 8-Methyl-7-[4-(4-piperidyloxy)phenyl]quinolin-2-ol, HCl

tert-Butyl4-[4-(2-methoxy-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate(750 mg. 1.7 mmol) in 4N HCl in dioxane (10 mL) was heated at 70° C. for12 h and concentrated. The solid was triturated with ether, collectedand dried to give 600 mg (97%) of a tan solid as the HCl salt. LCMS=335m/z (M+1); 1H NMR (DMSO-d6) δ 10.84 (br s, 1H), 8.76 (br s, 2H), 7.93(d, J=9.5 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.8 Hz, 2H), 7.09(d, J=8.8 Hz, 2H), 7.05 (d, J=8.0 Hz, 1H), 6.52 (d, J=9.5 Hz, 1H), 4.72(dt, J=7.2, 3.8 Hz, 1H), 3.26 (br s, 2H), 3.10 (br d, J=5.8 Hz, 2H),2.31 (s, 3H), 2.24-2.08 (m, 2H), 1.96-1.78 (m, 2H).

Step 3.N-Ethyl-4-[4-(2-hydroxy-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide

8-Methyl-7-[4-(4-piperidyloxy)phenyl]quinolin-2-ol HCl (100 mg, 0.27mmol), isocyanatoethane (38 mg, 0.43 mmol), diisopropylethylamine (0.14mL) in DCM (3 mL) was stirred at rt for 4 h. The mixture wasconcentrated, dissolved in EtOAc and washed with 1N Na₂CO₃ and brine andthen dried (MgSO₄). The product was chromatographed on Isco (12 g silicagel, 0-5% MeOH/DCM) to give a white solid. Analysis: LCMS m/z=406 (M+1);¹H NMR (DMSO-d₆ (deuterated dimethylsulfoxide)) δ: 10.82 (s, 1H), 7.92(d, J=9.5 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.8 Hz, 2H),7.10-6.97 (m, 3H), 6.57-6.45 (m, 2H), 4.59 (dt, J=8.1, 4.4 Hz, 1H),3.75-3.63 (m, 2H), 3.17-3.01 (m, 4H), 2.31 (s, 3H), 2.02-1.87 (m, 2H),1.59-1.46 (m, 2H), 1.01 (t, J=7.2 Hz, 3H)

The following examples were synthesized using the procedure of Example73, Method A.

Example 530.4-[4-(8-Methyl-7-quinolyl)phenoxy]-N-(2-pyrrolidin-1-ylethyl)piperidine-1-carboxamideHCl

LCMS m/z=459 (M+1); ¹H NMR (CHLOROFORM-d) δ: 8.99 (dd, J=4.3, 1.8 Hz,1H), 8.16 (dd, J=8.3, 1.8 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.47 (d,J=8.3 Hz, 1H), 7.41 (dd, J=8.2, 4.1 Hz, 1H), 7.33 (d, J=8.5 Hz, 2H),7.00 (d, J=8.8 Hz, 2H), 6.84 (br s, 1H), 4.61-4.52 (m, 1H), 3.89-3.78(m, 2H), 3.71-3.63 (m, 2H), 3.54-3.42 (m, 3H), 3.28-3.19 (m, 2H), 2.77(s, 3H), 2.17 (br s, 4H), 2.10-1.96 (m, 3H), 1.93-1.80 (m, 4H)

Example 531.4-[4-(8-Methyl-7-quinolyl)phenoxy]-N-(2-morpholinoethyl)piperidine-1-carboxamideHCl

LCMS m/z=475 (M+1); ¹H NMR (400 MHz, DMSO-d6) δ:10.62 (br s, 1H), 9.07(d, J=3.0 Hz, 1H), 8.66 (br s, 1H), 8.00 (br d, J=8.3 Hz, 1H), 7.75 (brs, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.8Hz, 2H), 7.03 (br s, 1H), 4.66 (dt, J=8.0, 4.2 Hz, 1H), 3.97 (br d,J=10.5 Hz, 4H), 3.79 (br t, J=11.3 Hz, 4H), 3.50 (br d, J=12.3 Hz, 2H),3.44 (br d, J=7.0 Hz, 2H), 3.24-3.02 (m, 7H), 2.70 (s, 3H), 1.98 (br d,J=8.5 Hz, 2H), 1.63-1.53 (m, 2H)

Example 532.(4-Isopropylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone,HCl

Step 1. 4-Nitrophenyl)4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate

8-Methyl-7-[4-(4-piperidyloxy)phenyl]quinoline (0.8 g, 2.51 mmol) in DCM(15 mL) was added TEA (0.70 mL, 5.03 mmol) and (4-nitrophenyl)carbonochloridate (0.66 g, 3.27 mmol) on an ice bath. The solution wasstirred for 2 h at rt and then concentrated. The residue was dissolvedin EtOAc and washed with 1N Na₂CO₃, and brine then dried over MgSO₄. Theproduct was purified by ISCO (80 g silica gel, 30-60% EtOAc/hexanes).The fractions containing pure product were concentrated to give a whitesolid (900 mg, 73%). This material was used in the next step. Analysis:LCMS m/z=484 (M+1); ¹H NMR (400 MHz, DCCl₃) δ: 9.00 (dd, J=4.3, 1.8 Hz,1H), 8.32-8.24 (m, 2H), 8.20-8.13 (m, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.47(d, J=8.3 Hz, 1H), 7.43 (dd, J=8.3, 4.3 Hz, 1H), 7.38-7.31 (m, 3H),7.10-6.99 (m, 2H), 4.68 (tt, J=6.2, 3.3 Hz, 1H), 3.96-3.63 (m, 4H), 2.78(s, 3H), 2.14-1.94 (m, 4H)

Step 2.(4-Isopropylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone,HCl

(4-Nitrophenyl)4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate (0.04 g,0.082 mmol), 1-isopropylpiperazine (0.042 g, 0.33 mmol), and 1,4-dioxane(1 mL) was heated at 125° C. for a total of 4 h on the microwave. Themixture was diluted in EtOAc, washed with 1N Na₂CO₃ and brine then driedover MgSO₄. The product was purified by ISCO (4 g, MeOH/DCM 0-10%) togive an oil. The HCl salt was synthesized by adding 2N HCl-ether to aDCM solution of base to give a light yellow solid (25 mg, 58%).Analysis: LCMS m/z=473 (M+1); ¹H NMR (400 MHz, DMSO-d6) δ: 10.61 (br s,1H), 9.07 (br d, J=3.3 Hz, 1H), 8.66 (br s, 1H), 8.00 (br d, J=8.3 Hz,1H), 7.75 (br s, 1H), 7.61 (br d, J=8.5 Hz, 1H), 7.40 (d, J=8.5 Hz, 2H),7.13 (d, J=8.5 Hz, 2H), 4.68 (br s, 1H), 3.66 (br d, J=13.6 Hz, 2H),3.59-3.44 (m, 3H), 3.40-3.27 (m, 4H), 3.15 (br t, J=9.5 Hz, 2H),3.07-2.95 (m, 2H), 2.70 (s, 3H), 1.99 (br s, 2H), 1.69-1.58 (m, 2H),1.28 (d, J=6.5 Hz, 6H).

Example 533.(4-Methyllpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone,HCl

(4-Nitrophenyl)4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate (0.1 g, 0.21mmol), 1-methylpiperazine (0.1 g, 1.0 mmol), and 1,4-dioxane (2 mL) washeated at 125° C. for a total of 4 h on the microwave. The mixture wasdiluted in EtOAc, washed with 1N Na₂CO₃ and brine then dried over MgSO₄.The product was purified by ISCO (4 g, MeOH/DCM 0-10%) to give an oil.The HCl salt was synthesized by adding 2N HCl-ether to a DCM solution ofbase, and concentrating to give a yellow salt (55 mg, 59%). Analysis:LCMS m/z=445 (M+1); ¹H NMR (400 MHz, DMSO-d6) δ: 10.75 (br s, 1H), 9.08(br d, J=3.5 Hz, 1H), 8.68 (br s, 1H), 8.01 (br d, J=8.8 Hz, 1H), 7.77(br s, 1H), 7.62 (br d, J=8.3 Hz, 1H), 7.40 (br d, J=8.5 Hz, 2H), 7.13(br d, J=8.8 Hz, 2H), 4.68 (br s, 1H), 3.66 (br d, J=14.1 Hz, 2H), 3.53(br d, J=13.3 Hz, 2H), 3.41-3.33 (m, 2H), 3.26-3.12 (m, 4H), 3.07-2.97(m, 2H), 2.80-2.76 (m, 3H), 2.71 (s, 3H), 1.99 (br s, 2H), 1.65 (br d,J=9.0 Hz, 2H).

Example 534.[4-[4-(8-Methyl-7-quinolyl)phenoxy]-1-piperidyl]-(4-morpholino-1-piperidyl)methanone,HCl

(4-Nitrophenyl)4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate (0.075 g,0.16 mmol), 4-(4-piperidyl)morpholine (0.13 g, 0.78 mmol) and1-methyl-2-pyrrolidinone (2.058 g, 2 mL, 20.76 mmol) was heated at 155°C. for 1.5 h on the microwave. The mixture was diluted in EtOAc, washedwith 1N Na₂CO₃ and brine then dried over MgSO₄. The product was purifiedby ISCO (4 g, MeOH/DCM 0-10%) to give an solid. This material wastriturated with ether and hexanes then collected to give a white solid(40 mg. 49%). Analysis: LCMS m/z=515 (M+1); ¹H NMR (CHLOROFORM-d) δ:8.99 (dd, J=4.3, 1.8 Hz, 1H), 8.16 (dd, J=8.3, 1.8 Hz, 1H), 7.70 (d,J=8.3 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.41 (dd, J=8.2, 4.1 Hz, 1H),7.37-7.31 (m, 2H), 7.01 (d, J=8.8 Hz, 2H), 4.55 (dt, J=7.1, 3.6 Hz, 1H),3.82-3.68 (m, 6H), 3.64-3.50 (m, 2H), 3.28-3.12 (m, 2H), 2.84-2.78 (m,2H), 2.77 (s, 3H), 2.57 (br s, 3H), 2.42-2.27 (m, 1H), 2.10-1.98 (m,2H), 1.90-1.81 (m, 4H), 1.55-1.43 (m, 2H)

Example 535. (4-Ethyllpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanonetosylate

(4-Nitrophenyl)4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate (0.1 g, 0.21mmol), 1-ethylpiperazine (0.12 g, 1.03 mmol), and1-methyl-2-pyrrolidinone (1 mL) was heated at 160° C. for 1 h on themicrowave. The mixture was diluted in EtOAc, washed with 1N Na₂CO₃ andbrine then dried over MgSO₄. The product was purified by ISCO (4 g,MeOH/DCM 0-10%) to give an oil. The tosylate salt was synthesized byadding p-toluenesulfonic acid monohydrate in acetone (2 mL) to anacetone solution of base and concentrating. The light yellow solid wassuspended in DCM and ether added, the product collected and dried undervacuum (75 mg, 68%). Analysis: LCMS m/z=459 (M+1); ¹H NMR (400 MHz,DMSO-d6) δ: 9.32 (br s, 1H), 9.02 (br d, J=3.0 Hz, 1H), 8.52 (br s, 1H),7.93 (br d, J=8.3 Hz, 1H), 7.65 (br s, 1H), 7.54 (br d, J=7.8 Hz, 1H),7.47 (d, J=8.0 Hz, 4H), 7.39 (d, J=8.5 Hz, 2H), 7.15-7.08 (m, 6H), 4.68(br s, 1H), 3.68 (br d, J=13.8 Hz, 2H), 3.54 (br d, J=14.3 Hz, 2H), 3.45(br d, J=11.5 Hz, 2H), 3.21-2.95 (m, 8H), 2.68 (s, 3H), 2.29 (s, 6H),1.99 (br s, 2H), 1.65 (br d, J=8.3 Hz, 2H), 1.22 (t, J=7.3 Hz, 3H)

Example 536.N-Ethyl-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

7-Methyl-6-[4-(4-piperidyloxy)phenyl]pyrazolo[1,5-a]pyridinedihydrochloride (0.08 g, 0.21 mmol) and triethylamine (0.09 mL) in DCM(3 mL) was added isocyanatoethane (0.03 g, 0.022 mL, 0.42 mmol)dropwise. After stirring at rt for 4 h the solution was concentrated,dissolved in EtOAc, washed with 1N Na₂CO₃ and brine and then dried overMgSO₄. The product was purified by ISCO (12 g silica gel, 40-90%EtOAc/hexanes), and crystallized from ether to give a white solid (60mg, 75%); LCMS m/z=379 (M+1); ¹H NMR (400 MHz, CHLOROFORM-d) δ: 8.03 (d,J=2.3 Hz, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.29 (d, J=8.5 Hz, 2H), 7.11 (d,J=9.0 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.59 (d, J=2.3 Hz, 1H), 4.56 (dt,J=6.8, 3.5 Hz, 1H), 4.43 (br s, 1H), 3.75-3.61 (m, 2H), 3.42-3.26 (m,4H), 2.75 (s, 3H), 2.00 (td, J=8.6, 3.9 Hz, 2H), 1.91-1.78 (m, 2H), 1.17(t, J=7.3 Hz, 3H).

Example 537.N-Isopropoxy-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

O-Isopropylhydroxylamine hydrochloride (0.073 g, 0.66 mmol), DCI (0.107g, 0.658 mmol) DIEA in dichloroethane (4 mL) was stirred for 2 h at rt.7-Methyl-6-[4-(4-piperidyloxy)phenyl]pyrazolo[1,5-a]pyridinedihydrochloride (0.125 g, 0.329 mmol) was added and stirred at rtovernight. The mixture was concentrated, dissolved in EtOAc, washed withbrine and then dried over MgSO₄. The product was purified by ISCO (12 gsilica gel, 40-90% EtOAc/hexanes). The product was crystallized fromether and hexanes to give a white solid (70 mg, 52%). LCMS m/z=409(M+1); ¹H NMR (400 MHz, DCCl₃) δ: 8.03 (d, J=2.3 Hz, 1H), 7.55-7.45 (m,1H), 7.34-7.27 (m, 2H), 7.11 (d, J=9.0 Hz, 1H), 7.05-6.96 (m, 2H), 6.93(s, 1H), 6.59 (d, J=2.3 Hz, 1H), 4.59 (tt, J=6.5, 3.3 Hz, 1H), 4.06(spt, J=6.2 Hz, 1H), 3.75-3.61 (m, 2H), 3.43 (ddd, J=13.4, 7.0, 3.9 Hz,2H), 2.75 (s, 3H), 2.07-1.95 (m, 2H), 1.93-1.80 (m, 2H), 1.25 (d, J=6.0Hz, 6H).

Example 538.N-Ethoxyoxy-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

Synthesized using by the method of Example 538 usingO-ethylhydroxylamine hydrochloride. LCMS m/z=395 (M+1); 1H NMR (400 MHz,CHLOROFORM-d) δ: 8.03 (d, J=2.3 Hz, 1H), 7.55-7.45 (m, 1H), 7.30 (d,J=8.5 Hz, 2H), 7.11 (d, J=9.0 Hz, 1H), 7.05-6.92 (m, 3H), 6.59 (d, J=2.3Hz, 1H), 4.59 (dt, J=6.5, 3.2 Hz, 1H), 3.93 (q, J=7.0 Hz, 2H), 3.75-3.62(m, 2H), 3.47-3.41 (m, 2H), 2.75 (s, 3H), 2.07-1.95 (m, 2H), 1.93-1.82(m, 2H), 1.27 (t, J=7.0 Hz, 3H)

Example 539.N-Methoxyoxy-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

Synthesized using by the method of Example 538 usingO-methylhydroxylamine hydrochloride. LCMS m/z=381 (M+1); 1H NMR (400MHz, CCCl₃) δ: 8.05 (d, J=2.0 Hz, 1H), 7.51 (d, J=9.0 Hz, 1H), 7.30 (d,J=8.5 Hz, 2H), 7.14 (d, J=9.0 Hz, 1H), 6.99 (d, J=8.5 Hz, 2H), 6.60 (d,J=2.3 Hz, 1H), 4.62-4.57 (m, 1H), 3.74 (s, 3H), 3.66 (br dd, J=8.7, 4.6Hz, 2H), 3.46-3.40 (m, 2H), 2.77 (s, 3H), 2.02-1.96 (m, 2H), 1.92-1.87(m, 2H)

Example 540.N-(Cyclopropylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide,HCl

1-Isocyanato-2-methylpropane (30.5 mg, 0.302 mmol) was added to asolution of 8-methyl-7-[4-(4-piperidyloxy)phenyl]quinolinedihydrochloride (80 mg, 0.25 mmol), and N,N-diisopropylethylamine (0.131mL, 0.751 mmol) in dichloromethane (3 mL) at 0° C. After stirring for 1h, the reaction was concentrated and partitioned between EtOAc and 1 MNa₂CO₃. The organic layer was washed with brine, and then dried overMgSO₄, filtered and concentrated in vacuo. The product was purified onISCO (12 g silica gel column, 45-90% EtOAc in hexanes) to yield an oil.The HCl salt was synthesized by adding 1 mL of 4M HCl-dioxane solutionto a methanol solution of base. The salt was concentrated to yieldN-(cyclopropylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamideHCl (72 mg, 63%). Analysis: LCMS m/z=416 (M+1); ¹H NMR (400 MHz, DCCl₃)δ: 9.46 (1H, br d, J=4.0 Hz), 8.86 (1H, d, J=8.0 Hz), 8.00 (1H, d, J=8.5Hz), 7.89-7.96 (1H, m), 7.83 (1H, d, J=8.5 Hz), 7.33 (2H, d, J=8.8 Hz),7.07 (2H, d, J=8.8 Hz), 4.64 (1H, dt, J=6.5, 3.0 Hz), 3.71 (2H, ddd,J=13.0, 8.8, 3.5 Hz), 3.32-3.46 (2H, m), 3.13 (2H, d, J=7.3 Hz), 3.08(1H, s), 3.04-3.10 (1H, m), 2.07-2.22 (2H, m), 1.86-2.02 (3H, m),0.93-1.10 (1H, m), 0.46-0.62 (2H, m), 0.15-0.27 (2H, m), 0.04-0.05 (1H,m).

The following examples were made using the previous procedure.

Example 541.N-Isobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide,HCl

Using 8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline 2HCl and1-isocyanato-2-methylpropane. Analysis: LCMS m/z=418 (M+1); ¹H NMR (400MHz, DCCl₃) δ: 9.46 (1H, br d, J=4.3 Hz), 8.87 (1H, d, J=7.3 Hz), 8.00(1H, d, J=8.5 Hz), 7.93 (1H, dd, J=8.3, 5.3 Hz), 7.83 (1H, d, J=8.5 Hz),7.30-7.38 (2H, m), 7.02-7.13 (2H, m), 4.68 (1H, dt, J=6.0, 3.0 Hz), 3.73(2H, ddd, J=13.0, 9.3, 3.5 Hz), 3.31-3.47 (2H, m), 3.12 (2H, d, J=6.8Hz), 3.07 (3H, s), 2.15-2.29 (2H, m), 1.98-2.11 (2H, m), 1.84 (1H, dt,J=13.5, 6.7 Hz), 0.96 (6H, d, J=6.8 Hz).

Example 542.N-(2-Methoxyethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamideHCl

Using 8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline 2HCl and1-isocyanato-2-methoxyethane. Analysis: LCMS m/z=420 (M+1); ¹H NMR (400MHz, DCCl₃) δ: 9.46 (1H, br s), 8.96 (1H, br d, J=4.3 Hz), 7.91-8.18(2H, m), 7.83 (1H, br d, J=8.0 Hz), 7.24-7.40 (2H, m), 7.06 (2H, br d,J=8.3 Hz), 4.80-5.28 (1H, m), 4.62 (1H, br s), 3.60-3.87 (2H, m),3.24-3.59 (11H, m), 3.06 (3H, s), 1.95-2.22 (2H, m), 1.87 (2H, br d,J=6.5 Hz).

Example 543.N-Isopropoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide

At 0° C., 8-methyl-7-[4-(4-piperidyloxy)phenyl]quinolone 2 HCl (100 mg,0.31 mmol) in DCM (3 mL) was treated with N,N-diisopropylethylamine(0.219 mL, 1.26 mmol) and then triphosgene (95.1 mg, 0.314 mmol). Uponcompetition of the acid chloride, the reaction was partitioned betweenCH₂Cl₂ and brine, the organic layers separated and dried over MgSO₄,then concentrated in vacuo to a brown oil. To the oil in 1,2dichloroethane, was added DIPEA (0.219 mL, 1.26 mmol), and thenO-isopropylhydroxylamine hydrochloride (72 mg, 0.63 mmol) and heated to70° C. for 20 h. The reaction was concentrated, dissolved in EtOAc,washed with brine, and then dried over MgSO₄. The product was purifiedby Gilson, (10-55% ACN with 0.1% TFA/H₂O with 0.1% TFA). The product wasconcentrated with toluene, then free based with Na₂CO₃ to yieldN-isopropoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide(39 mg, 30%). LCMS m/z=420 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.50 (1H,s), 8.97 (1H, dd, J=4.3, 1.8 Hz), 8.36 (1H, dd, J=8.3, 1.8 Hz), 7.85(1H, d, J=8.3 Hz), 7.55 (1H, dd, J=8.2, 4.1 Hz), 7.47 (1H, d, J=8.5 Hz),7.37 (2H, d, J=8.5 Hz), 7.10 (2H, d, J=8.8 Hz), 4.63 (1H, dt, J=8.2, 4.3Hz), 3.88 (1H, quin, J=6.2 Hz), 3.55-3.72 (2H, m), 3.04-3.25 (2H, m),2.68 (3H, s), 1.79-2.09 (2H, m), 1.56 (2H, ddt, J=12.9, 8.6, 4.3, 4.3Hz), 1.23 (1H, s), 1.12 (6H, d, J=6.3 Hz).

Example 544.N-Isobutoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide

Step 1

8-Methyl-7-[4-(4-piperidyloxy)phenyl]quinoline (300 mg, 0.9422 mmol) inDCM (10 mL) at 0° C., was treated with DIPEA (2 equiv., 1.884 mmol) andtriphosgene (1 equiv., 0.942 mmol). After 2 h, the solution waspartitioned between DCM and brine, the organic layer dried over MgSO₄,filtered and concentrated to yield4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl chloride.

Step 2

4-[4-(8-Methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl chloride (0.10g, 0.26 mmol) in DCE (2 mL), was added DIPEA (0.22 mL, 1.26 mmol), ando-isobutylhydroxylamine HCl (0.068 g, 0.53 mmol). The reaction washeated to 70° C. for 5 h, cooled to rt diluted with EtOAc and washedwith water and brine then dried over MgSO₄. The product was purified byGILSON (Gemini-NX-5u, C18 110A 150×30 mm 5 micron column), (15-60%ACN/H₂O with 0.1% TFA). The fractions with product were concentrated,and free based with Na₂CO₃ to yieldN-isobutoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide(39 mg, 34%). Analysis: LCMS m/z=434 (M+1); 1H NMR (400 MHz, DMSO-d₆) δ:9.65 (1H, s), 8.97 (1H, dd, J=4.1, 1.9 Hz), 8.36 (1H, dd, J=8.3, 1.8Hz), 7.85 (1H, d, J=8.3 Hz), 7.55 (1H, dd, J=8.2, 4.1 Hz), 7.47 (1H, d,J=8.5 Hz), 7.34-7.40 (2H, m), 7.06-7.13 (2H, m), 4.63 (1H, dt, J=7.9,4.1 Hz), 3.55-3.71 (2H, m), 3.49 (2H, d, J=6.8 Hz), 3.05-3.20 (2H, m),2.68 (3H, s), 1.78-2.03 (3H, m), 1.56 (2H, td, J=8.5, 4.5 Hz), 0.90 (6H,d, J=6.5 Hz).

Example 545.N-(2-Dimethylaminoethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamideHCl

Prepared using 4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonylchloride and N,N-dimethylethylenediamine. Analysis: LCMS m/z=433 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ: 9.77 (1H, br s), 8.97-9.06 (1H, m), 8.53(1H, br s), 7.94 (1H, br d, J=9.0 Hz), 7.66 (1H, br s), 7.55 (1H, d,J=8.3 Hz), 7.39 (2H, d, J=8.8 Hz), 7.12 (2H, d, J=8.8 Hz), 6.86-6.99(1H, m), 4.59-4.75 (1H, m), 3.67-3.81 (2H, m), 3.32-3.45 (2H, m),3.03-3.27 (4H, m), 2.80 (6H, d, J=5.0 Hz), 2.69 (3H, s), 1.97 (2H, brs), 1.48-1.71 (2H, m)

Example 546. 2-Morpholinoethyl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate 2HCl

Prepared using 4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonylchloride and 2-morpholinoethanol. Analysis: LCMS m/z=460 (M+1); ¹H NMR(400 MHz, DMSO-d₆) δ:11.70 (1H, br s), 9.17 (1H, dd, J=4.8, 1.3 Hz),8.92 (1H, br d, J=6.8 Hz), 8.03-8.22 (1H, m), 7.92 (1H, br dd, J=7.9,4.9 Hz), 7.61-7.83 (1H, m), 7.32-7.52 (2H, m), 7.12-7.18 (2H, m), 4.71(1H, dt, J=7.8, 4.1 Hz), 4.34-4.49 (2H, m), 3.63-4.05 (6H, m), 3.23-3.47(6H, m), 3.07-3.17 (2H, m), 2.75 (3H, s), 2.01 (2H, dt, J=6.7, 3.0 Hz),1.52-1.75 (2H, m).

Example 547. 2-Pyrrolidin-1-ylethyl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate, 2HCl

Synthesized using4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl chloride andN-(2-hydroxyethyl)pyrrolidine. Analysis: LCMS m/z=460 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ: 11.28 (1H, br s), 9.17 (1H, dd, J=4.9, 1.4 Hz), 8.92(1H, br d, J=7.5 Hz), 8.12 (1H, d, J=8.5 Hz), 7.91 (1H, br dd, J=7.8,5.0 Hz), 7.72 (1H, d, J=8.5 Hz), 7.34-7.51 (2H, m), 7.15 (2H, d, J=8.8Hz), 4.71 (1H, dt, J=7.7, 4.0 Hz), 4.28-4.43 (2H, m), 3.69-3.94 (2H, m),3.55 (2H, br dd, J=10.3, 5.0 Hz), 3.26-3.48 (4H, m), 2.91-3.12 (2H, m),2.75 (3H, s), 1.81-2.10 (6H, m), 1.54-1.73 (2H, m).

Example 548.N-[2-(1H-Imidazol-4-yl)ethyl]-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide,2HCl

Synthesized using4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl chloride andhistamine. Analysis: LCMS m/z=456 (M+1); ¹NMR (400 MHz, DMSO-d₆) δ:14.52 (1H, br s), 14.28 (1H, br s), 9.12 (1H, br d, J=3.3 Hz), 9.03 (1H,s), 8.79 (1H, br s), 8.06 (1H, br d, J=8.5 Hz), 7.84 (1H, br s), 7.67(1H, d, J=8.5 Hz), 7.45 (1H, s), 7.41 (2H, d, J=8.8 Hz), 7.13 (2 H, d,J=8.8 Hz), 6.80 (1H, br s), 4.64 (1H, dt, J=8.2, 4.2 Hz), 3.61-3.77 (2H,m), 3.35 (2H, br t, J=6.7 Hz), 3.07-3.20 (2H, m), 2.82 (2H, t, J=6.8Hz), 2.73 (3H, s), 1.93 (2H, br dd, J=10.7, 5.6 Hz), 1.45-1.61 (2H, m).

Example 549.4-[4-(8-Methyl-7-quinolyl)phenoxy]-N-tetrahydropyran-4-yl-piperidine-1-carboxamide,HCl

Synthesized using4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl chloride and4-aminotetrahydropyran. Analysis: LCMS m/z=446 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ: 9.03-9.17 (1H, m), 8.76 (1H, br s), 8.05 (2H, br d, J=8.3Hz), 7.81 (1H, br s), 7.65 (2H, d, J=8.5 Hz), 7.28-7.52 (2H, m),7.06-7.21 (2H, m), 6.33 (2H, br s), 4.63 (1H, br d, J=4.3 Hz), 3.83 (2H,br dd, J=11.9, 2.1 Hz), 3.54-3.78 (3H, m), 3.31 (2H, td, J=11.7, 1.9Hz), 3.05-3.21 (2H, m), 2.71 (3H, s), 1.86-2.03 (2H, m), 1.68 (2H, brdd, J=12.4, 2.4 Hz), 1.34-1.60 (4H, m).

Example 550. Isobutyl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate, HCl

Isobutyl chloroformate (0.085 mL, 0.64 mmol) was added to a solution of8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline (100 mg, 0.3141 mmol) andDIPEA (0.11 mL) in 1,2-dichloroethane (5 mL) at 0° C. After 0.5 h, thereaction was diluted with EtOAc and washed with water, H₂O and brine;then dried over MgSO₄. The product was purified by GILSON (Gemini-NX-5u,C18 110A 150×30 mm 5 micron column), (5-60% ACN/H₂O with 0.1% TFA) toyield isobutyl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate HCl (15 mg,10%) Analysis: LCMS m/z=419 (M+1); 1H NMR (400 MHz, DMSO-d₆) δ: 9.04(1H, dd, J=4.4, 1.6 Hz), 8.58 (1H, br s), 7.96 (1H, br d, J=8.3 Hz),7.62-7.75 (1H, m), 7.57 (1H, d, J=8.3 Hz), 7.33-7.45 (2H, m), 7.04-7.17(2H, m), 4.68 (1H, dt, J=8.0, 4.0 Hz), 3.81 (4H, d, J=6.5 Hz), 3.29 (2H,br s), 2.69 (3H, s), 1.93-2.07 (2H, m), 1.88 (1H, dt, J=13.4, 6.7 Hz),1.60 (2H, dtd, J=12.9, 8.7, 8.7, 4.1 Hz), 0.90 (6H, d, J=6.8 Hz).

Example 551. Allyl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate, HCl

Synthesized using 8-methyl-7-[4-(4-piperidyloxy)phenyl]quinolone 2 HCland allyl chloroformate. Analysis: LCMS m/z=403 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ: 9.17 (1H, dd, J=4.8, 1.3 Hz), 8.94 (1H, br d, J=7.3 Hz),8.13 (1H, d, J=8.5 Hz), 8.04-8.21 (1H, m), 7.93 (1H, br dd, J=7.9, 5.1Hz), 7.73 (1H, d, J=8.5 Hz), 7.42 (2H, d, J=8.5 Hz), 7.15 (2H, d, J=8.5Hz), 5.80-6.12 (1H, m), 5.30 (1H, dq, J=17.3, 1.7 Hz), 5.21 (1H, dq,J=10.5, 1.5 Hz), 4.70 (1H, dt, J=7.8, 4.1 Hz), 4.55 (2H, dt, J=5.3, 1.5Hz), 3.61-3.88 (2H, m), 3.32 (2H, br s), 2.75 (3H, s), 2.00 (2H, ddd,J=9.5, 6.1, 2.8 Hz), 1.45-1.73 (2H, m).

Example 552.N-Cyclobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamideHCl

Synthesized using4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl chloride andcyclobutylamine. Analysis: LCMS m/z=416 (M+1); ¹H NMR (400 MHz, DMSO-d₆)δ: 9.15 (1H, dd, J=4.8, 1.5 Hz), 8.88 (1H, br d, J=7.3 Hz), 8.10 (1H, brd, J=8.5 Hz), 7.89 (1H, br dd, J=7.9, 4.9 Hz), 7.71 (1H, d, J=8.5 Hz),7.32-7.50 (2H, m), 7.00-7.20 (2H, m), 6.67 (1H, br s), 4.63 (1H, dt,J=8.2, 4.3 Hz), 4.11 (1H, brt, J=8.4 Hz), 3.57-3.85 (2H, m), 2.92-3.26(2H, m), 2.73 (3H, s), 2.01-2.19 (2H, m), 1.77-1.99 (4H, m), 1.36-1.68(4H, m).

Example 553: Cyclopropylmethyl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate HCl

Synthesized using4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl chloride andcyclopropanemethanol. Analysis: LCMS m/z=417 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ: 9.11 (1H, dd, J=4.6, 1.4 Hz), 8.77 (1H, br s), 8.05 (1H, brd, J=8.3 Hz), 7.75-7.95 (1H, m), 7.66 (1H, d, J=8.3 Hz), 7.30-7.50 (2H,m), 7.06-7.27 (2H, m), 4.68 (1H, tt, J=7.8, 3.8 Hz), 3.86 (2H, d, J=7.0Hz), 3.68-3.80 (2H, m), 3.29 (2H, br s), 2.72 (3H, s), 1.84-2.06 (2H,m), 1.61 (2H, dtd, J=12.9, 8.7, 8.7, 4.0 Hz), 1.03-1.22 (1H, m),0.38-0.59 (2H, m), 0.14-0.36 (2H, m).

Example 554.4-[4-(8-Methyl-7-quinolyl)phenoxy]piperidine-l-carbohydroxamic acid, HCl

Synthesized using4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl chloride, andhydroxylamine HCl. Analysis: LCMS m/z=378 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ: 9.13 (1H, br d, J=3.8 Hz), 8.84 (1H, br s), 8.08 (1H, br d,J=8.3 Hz), 7.86 (1H, br s), 7.69 (1H, br d, J=8.3 Hz), 7.37-7.44 (2H,m), 7.09-7.18 (2H, m), 4.66 (1H, dt, J=8.0, 4.2 Hz), 3.57-3.77 (2H, m),3.03-3.22 (2H, m), 2.72 (3H, s), 1.87-2.08 (2H, m), 1.55 (2H, td, J=8.6,4.4 Hz).

Example 555. 2-Methoxyethyl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate, HCl

Synthesized using 8-methyl-7-[4-(4-piperidyloxy)phenyl]quinolone and2-methoxyethyl chloroformate. Analysis: LCMS m/z=421 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ: 9.15 (1H, dd, J=4.8, 1.3 Hz), 8.89 (1H, br s), 8.11(1H, br d, J=8.5 Hz), 7.81-7.95 (1H, m), 7.71 (1H, d, J=8.3 Hz),7.32-7.48 (2H, m), 7.08-7.22 (2H, m), 4.69 (1H, dt, J=7.8, 4.1 Hz),4.01-4.21 (2H, m), 3.68-3.85 (2H, m), 3.45-3.63 (2H, m), 3.28 (5H, s),2.73 (3H, s), 1.99 (2H, ddd, J=9.6, 6.0, 3.0 Hz), 1.61 (2H, dtd, J=12.9,8.7, 8.7, 3.9 Hz).

Example 556. Tetrahydropyran-4-yl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate

Step 1

Added pyridine (0.317 mL, 3.92 mmol) to a solution of triphosgene (0.326g, 1.08 mmol) in THF (10 mL) at 0° C. and stirred for 10 min, thentetrahydropyran-4-ol (200 mg, 1.958 mmol), was added and stirred 45 minwhile warming to rt. The reaction was concentrated, dissolved in EtOAc(20 mL) and washed with water (20 mL) and then brine. The EtOAc layerwas dried over MgSO₄, filtered and concentrated to yieldtetrahydropyran-4-yl carbonochloridate.

Step 2

Synthesized using 8-methyl-7-[4-(4-piperidyloxy)phenyl]quinolone andtetrahydropyran-4-yl carbonochloridate. Analysis: LCMS m/z=447 (m+1); ¹HNMR (400 MHz, DMSO-d₆) δ: 8.97 (1 h, dd, j=4.1, 1.9 hz), 8.37 (1 h, dd,j=8.2, 1.9 hz), 7.85 (1 h, d, j=8.3 hz), 7.55 (1 h, dd, j=8.2, 4.1 hz),7.48 (1 h, d, j=8.5 hz), 7.34-7.41 (2 h, m), 7.07-7.15 (2 h, m), 4.76 (1h, tt, j=8.3, 4.1 hz), 4.67 (1 h, dt, j=7.8, 4.1 hz), 3.69-3.86 (4 h,m), 3.47 (2 h, ddd, j=11.6, 8.7, 3.0 hz), 3.34 (2 h, br s), 2.68 (3 h,s), 1.93-2.07 (2 h, m), 1.79-1.92 (2 h, m), 1.45-1.69 (4 h, m).

Example 557. Tetrahydropyran-3-yl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate

Synthesized using 8-methyl-7-[4-(4-piperidyloxy)phenyl]quinolone andtetrahydropyran-3-yl carbonochloridate by the method of Example 557.Analysis: LCMS m/z=447 (M+1); 1H NMR (400 MHz, DMSO-d₆) δ: 8.97 (1H, dd,J=4.3, 1.8 Hz), 8.37 (1H, dd, J=8.3, 1.8 Hz), 7.85 (1H, d, J=8.5 Hz),7.55 (1H, dd, J=8.2, 4.1 Hz), 7.48 (1H, d, J=8.5 Hz), 7.38 (2H, d, J=8.5Hz), 7.11 (2H, d, J=8.8 Hz), 4.61-4.75 (1H, m), 4.56 (1H, dt, J=6.0, 3.0Hz), 3.65-3.85 (3H, m), 3.55 (2H, t, J=5.3 Hz), 3.46 (1H, dd, J=11.7,5.6 Hz), 3.33 (2H, s), 2.68 (3H, s), 1.85-2.06 (3H, m), 1.42-1.81 (5H,m).

Example 558.[4-[4-(8-Methyl-7-quinolyl)phenoxy]-1-piperidyl]-(oxazinan-2-yl)methanone

Synthesized using4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl chloride and1,2-oxazinane HCl. Analysis: LCMS m/z=432 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ: 8.97 (1H, dd, J=4.3, 1.8 Hz), 8.37 (1H, dd, J=8.3, 1.8 Hz),7.85 (1H, d, J=8.5 Hz), 7.52-7.61 (1H, m), 7.51-7.52 (1H, m), 7.48 (1H,d, J=8.3 Hz), 7.37 (2H, d, J=8.8 Hz), 7.11 (2H, d, J=8.8 Hz), 4.68 (1H,tt, J=7.9, 3.7 Hz), 3.90 (2H, t, J=4.9 Hz), 3.65-3.78 (2H, m), 3.21-3.30(4H, m), 2.68 (3H, s), 2.01 (2H, ddd, J=9.5, 5.9, 3.1 Hz), 1.54-1.74(6H, m).

Example 559. Tetrahydrofuran-3-yl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate

Synthesized using 8-methyl-7-[4-(4-piperidyloxy)phenyl]quinolone andtetrahydrofuran-3-yl carbonochloridate. Analysis LCMS m/z=433 (M+1); ¹HNMR (400 MHz, DMSO-d₆) δ: 8.97 (1H, dd, J=4.3, 1.8 Hz), 8.36 (1H, dd,J=8.3, 2.0 Hz), 7.85 (1H, d, J=8.5 Hz), 7.52-7.60 (1H, m), 7.48 (1H, d,J=8.5 Hz), 7.37 (2H, d, J=8.8 Hz), 7.11 (2H, d, J=8.8 Hz), 5.15 (1H, td,J=4.3, 2.1 Hz), 4.58-4.72 (1H, m), 3.63-3.90 (6H, m), 3.15-3.42 (2H, m),2.68 (3H, s), 2.05-2.20 (1H, m), 1.84-2.03 (3H, m), 1.61 (2H, ddt,J=12.8, 8.6, 4.4, 4.4 Hz).

Example 560.N-(Cyclobutylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide

Synthesized using4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl chloride andcyclobutylmethylamine. Analysis: LCMS m/z=430 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ: 8.97 (1H, dd, J=4.3, 1.8 Hz), 8.37 (1H, dd, J=8.3, 1.8 Hz),7.85 (1H, d, J=8.3 Hz), 7.55 (1H, dd, J=8.3, 4.3 Hz), 7.48 (1H, d, J=8.5Hz), 7.32-7.40 (2H, m), 7.00-7.16 (2H, m), 6.52 (1H, t, J=5.5 Hz), 4.61(1H, dt, J=8.3, 4.2 Hz), 3.64-3.83 (2H, m), 2.93-3.20 (4H, m), 2.68 (3H,s), 2.40 (1H, dq, J=15.0, 7.5 Hz), 1.88-2.02 (4H, m), 1.73-1.87 (2H, m),1.41-1.71 (4H, m).

Example 561. Cyclobutyl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxylate

Synthesized using 8-methyl-7-[4-(4-piperidyloxy)phenyl]quinolone andcyclobutyl carbonochloridate. Analysis: LCMS m/z=417 (M+1); 1H NMR (400MHz, DMSO-d₆) δ: 8.97 (1H, dd, J=4.1, 1.9 Hz), 8.37 (1H, dd, J=8.2, 1.9Hz), 7.85 (1H, d, J=8.3 Hz), 7.55 (1H, dd, J=8.2, 4.1 Hz), 7.48 (1H, d,J=8.5 Hz), 7.37 (2H, d, J=8.8 Hz), 7.10 (2H, d, J=8.8 Hz), 4.84 (1H, dd,J=7.9, 7.2 Hz), 4.65 (1H, dt, J=8.0, 4.2 Hz), 3.73 (2H, br d, J=12.8Hz), 3.34 (6H, br s), 2.63-2.77 (3H, m), 2.16-2.33 (2H, m), 1.88-2.05(4H, m), 1.46-1.80 (4H, m)

Example 562.Azepan-1-yl-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone

Synthesized using4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl chloride andhexamethyleneimine. Analysis: LCMS m/z=444 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ: 8.97 (1H, dd, J=4.1, 1.9 Hz), 8.36 (1H, dd, J=8.3, 2.0 Hz),7.85 (1H, d, J=8.3 Hz), 7.55 (1H, dd, J=8.2, 4.1 Hz), 7.47 (1H, d, J=8.5Hz), 7.37 (2H, d, J=8.8 Hz), 7.10 (2H, d, J=8.8 Hz), 4.61 (1H, dt,J=8.0, 4.2 Hz), 3.20-3.44 (8H, m), 2.97 (2H, ddd, J=12.9, 9.5, 2.9 Hz),2.68 (3H, s), 1.93-2.08 (2H, m), 1.58-1.77 (6H, m), 1.36-1.55 (4H, m).

Example 563.N-Butyl-4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

Step 1. tert-Butyl4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxylate

Palladium acetate (0.046 g, 0.205 mmol), triphenylphosphine (0.202 g,0.770 mmol) and 1,4-dioxane (10 g, 9 mL, 100 mmol) were combined in aflask and stirred for 40 min under nitrogen.6-Bromo-5-chloroimidazo[1,2-a]pyridine (1.008 g, 4.35 mmol), tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]piperidine-1-carboxylate(1.514 g, 3.754 mmol), 1 M Na₂CO₃ in water (14.9 mL, 10 mmol) and DMF(10 g, 20 mL, 200 mmol) were then added. The reaction was purged withargon and heated at 80° C. under nitrogen for 4 h. The reaction was thencooled to rt, diluted with ETOAc and washed with 1N Na₂CO₃, and brine,then dried over sodium sulfate, filtered and concentrated. The residuewas purified by Isco normal phase chromatography, eluting withEtOAc/heptane to give an off-white solid (519 mg, 70%). LC-MS: m/z=428(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (m, 1H), 7.78 (m, 1H), 7.73 (d,1H, J=9.2 Hz), 7.48 (m, 2H), 7.38 (d, 1H, J=9.2 Hz), 7.13 (m, 2H),4.68-4.64 (m, 1H), 3.74-3.69 (m, 2H), 3.28-3.20 (m, 2H), 2.01-1.96 (m,2H), 1.62-1.54 (m, 2H), 1.44 (s, 9H).

Step 2. 5-chloro-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine

tert-Butyl4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxylate(0.519 g, 1.213 mmol) and aqueous HCl (6 M) (3 mL, 18 mmol) werecombined in a flask and stirred at RT for 2 h. The reaction wasconcentrated; the residue was dissolved in EtOAc and washed with NaHCO₃solution, water and brine. The aqueous phase was back extracted severaltimes with EtOAc. The organic phase was dried over MgSO₄, filtered andconcentrated to give an off-white solid (330 mg, 79%). LC-MS: m/z=328(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.10 (m, 1H), 7.78 (d, 1H, J=1.3Hz), 7.72 (m, 1H), 7.46 (m, 2H), 7.37 (d, 1H, J=9.2 Hz), 7.09 (m, 2H),4.52-4.46 (m, 1H), 3.01-2.96 (m, 2H), 2.65-2.59 (m, 2H), 1.99-1.95 (m,2H), 1.55-1.46 (m, 2H).

Step 3.N-Butyl-4-[4-(5-chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

5-Chloro-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine (0.068 g,0.2074 mmol), DIPEA (0.081 g, 0.11 mL, 0.61 mmol) and DCM (3 g, 2 mL, 40mmol) were combined in a vial. Butyl isocyanate (0.030 g, 0.034 mL, 0.30mmol) was added, and the reaction was stirred at rt for 17 h. Thereaction was washed with 1 N aqueous Na₂CO₃ solution, then brine. Theorganic layer was dried over MgSO₄, filtered and concentrated. Theresidue was purified by Isco normal phase chromatography eluting with 0%to 8% methanol in DCM to give a white solid (62 mg, 70%). mp: 171-177°C.; HPLC 5.25 min. rt=2.359 min.; LC-MS: m/z=427 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ: 8.08 (m, 1H), 7.76 (d, 1H, J=1.3 Hz), 7.70 (m, 1H), 7.46 (m,2H), 7.36 (m, 1H), 7.10 (m, 2H), 6.48 (m, 1H), 4.64-4.60 (m, 1H),3.72-3.69 (m, 2H), 3.14-3.08 (m, 2H), 3.04-2.99 (m, 2H), 1.93 (m, 2H),1.56-1.47 (m, 2H), 1.43-1.36 (m, 2H), 1.34-1.22 (m, 2H), 0.88 (m, 3H).

Example 564.4-[4-(5-Chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-ethyl-piperidine-1-carboxamide

The title compound, a white solid, was prepared in a manner similar tothe procedure used to prepare Example 564 in 68% yield. mp: 189-193° C.;HPLC 5.25 min. rt=1.970 min.; LC-MS: m/z=399 (M+1); 1H NMR (400 MHz,DMSO-d₆) δ: 8.08 (s, 1H), 7.76 (d, 1H, J=1.3 Hz), 7.70 (d, 1H, J=9.3Hz), 7.46 (m, 2H), 7.36 (d, 1H, J=9.2 Hz), 7.10 (m, 2H), 6.50 (m, 1H),4.64-4.60 (m, 1H), 3.72-3.68 (m, 2H), 3.14-3.02 (m, 4H), 1.94 (m, 2H),1.56-1.49 (m, 2H), 1.01 (m, 3H).

Example 565.4-[4-(5-Chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-isobutyl-piperidine-1-carboxamide

This compound was prepared in a manner similar to the proceduredescribed in Example 564 in 67% yield. mp: 201° C.; LC-MS: m/z=427(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.08 (s, 1H), 7.76 (d, 1H, J=1.2Hz), 7.70 (d, 1H, J=9.2 Hz), 7.46 (m, 2H), 7.36 (d, 1H, J=9.2 Hz), 7.10(m, 2H), 6.54 (m, 1H), 4.65-4.60 (m, 1H), 3.75-3.71 (m, 2H), 3.15-3.09(m, 2H), 2.86-2.83 (m, 2H), 1.95-1.91 (m, 2H), 1.73-1.67 (m, 1H),1.55-1.47 (m, 2H), 0.84-0.82 (d, 6H, J=6.7 Hz).

Example 566.4-[4-(5-Chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-propyl-piperidine-1-carboxamide

The title compound was prepared in a manner similar to the procedureused to prepare Example 564 to give a white solid in 56% yield. mp: 184°C.; LC-MS: m/z=413 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.08 (s, 1H),7.76 (d, 1H, J=1.3 Hz), 7.70 (m, 1H), 7.48-7.44 (m, 2H), 7.36 (d, 1H,J=9.2 Hz), 7.10 (m, 2H), 6.51 (m, 1H), 4.65-4.60 (m, 1H), 3.74-3.68 (m,2H), 3.15-3.08 (m, 2H), 3.01-2.96 (m, 2H), 1.93 (m, 2H), 1.56-1.47 (m,2H), 1.46-1.37 (m, 2H), 0.85-0.81 (m, 3H).

Example 567.4-[4-(5-Chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-(2-methoxyethyl)piperidine-1-carboxamide

The title compound was prepared in a manner similar to the procedureused to prepare Example 564 in 30% yield. mp: 135-138° C.; LC-MS:m/z=429 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.09 (s, 1H), 7.76 (d, 1H,J=1.2 Hz), 7.70 (d, 1H, J=9.6 Hz), 7.45 (m, 2H), 7.36 (d, 1H, J=9.2 Hz),7.10 (m, 2H), 6.58 (m, 1H), 4.65-4.60 (m, 1H), 3.73-3.69 (m, 2H),3.37-3.27 (m, 2H), 3.24 (s, 3H), 3.20-3.09 (m, 4H), 1.94 (m, 2H),1.55-1.49 (m, 2H).

Example 568.4-[4-(5-Chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-(cyclopropylmethyl)-piperidine-1-carboxamide

The title compound was prepared in a manner similar to the procedureused to prepare Example 564 in 75% yield. mp: 183° C.-185° C.; LC-MS:m/z=425 (M+1); 1H NMR (400 MHz, DMSO-d₆) δ: 8.08 (s, 1H), 7.76 (d, 1H,J=0.3 Hz), 7.70 (d, 1H, J=9.1 Hz), 7.46 (m, 2H), 7.36 (d, 1H, J=9.2 Hz),7.11 (m, 2H), 6.59 (m, 1H), 4.65-4.60 (m, 1H), 3.74-3.69 (m, 2H),3.16-3.09 (m, 2H), 2.93-2.90 (m, 2H), 1.96-1.93 (m, 2H), 1.57-1.49 (m,2H), 0.98-0.88 (m, 1H), 0.39-0.35 (m, 2H), 0.16-0.13 (m, 2H)

Example 569.4-[4-(5-Chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-isopropoxy-piperidine-1-carboxamide

5-Chloro-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine HCl (0.053g, 0.1455 mmol) and TEA (0.08 mL, 0.574 mmol) in DCM (2 mL) was addedtriphosgene (0.043 g, 0.144904 mmol) and the reaction stirred at rt for2 h. Additional portions of triphosgene (25 mg) and TEA (20 uL) wereadded, the reaction was stirred for additional 30 min, thenconcentrated. The residue was dissolved in 1,2-dichloroethane (3 mL) andDIPEA (0.11 mL, 0.631 mmol) was added followed byO-isopropylhydroxylamine HCl (0.041 g, 0.36748 mmol). The reaction washeated at 70° C. for 5 h then stirred at rt for 16 h. The reaction wasconcentrated, diluted with EtOAc, washed with 1N aqueous Na₂CO₃, andthen brine. The organic phase was dried over MgSO₄, filtered andconcentrated. The residue was purified by Isco normal phasechromatography (methanol/DCM) then further purified by preparatory HPLCand lyophilized. The lyophilized material was diluted with EtOAc, washedwith 1 N aqueous Na₂CO₃, then brine, dried over magnesium sulfate,filtered and concentrated to yield a white solid (24 mg, 37%). mp: 175°C.; LC-MS: m/z=429 (M+1); ¹H NMR (400 MHz, MeOD) δ: 8.04 (s, 1H), 7.72(s, 1H), 7.63 (d, 1H, J=9.2 Hz), 7.45-7.39 (m, 3H), 7.08 (m, 2H),4.70-4.65 (m, 1H), 3.99-3.93 (m, 1H), 3.38-3.33 (m, 2H), 2.04-1.98 (m,2H), 1.79-1.71 (m, 2H), 1.21 (d, 6H, J=6.2 Hz).

Example 570.4-[4-(5-Chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-isopropyl-piperidine-1-carboxamide

The title compound was prepared in a manner similar in 45% yield. mp:220° C.; LC-MS: m/z=413 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.09 (s,1H), 7.76 (d, 1H, J=1.3 Hz), 7.72-7.69 (m, 1H), 7.36 (d, 1H, J=9.2 Hz),7.11 (m, 2H), 6.21 (d, 1H, J=7.6 Hz), 4.63-4.59 (m, 1H), 3.79-3.69 (m,3H), 3.13-3.07 (m, 2H), 1.95-1.92 (m, 2H), 1.56-1.47 (m, 2H), 1.06 (d,6H, J=6.6 Hz).

Example 571.4-[4-(5-Chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-isobutoxy-piperidine-1-carboxamide

The title compound was prepared in a manner similar in 19% yield. mp:157° C.; LC-MS: m/z=443 (M+1); ¹H NMR (400 MHz, MeOD) δ: 8.04 (s, 1H),7.72 (d, 1H, J=1.3 Hz), 7.63 (d, 1H, J=9.2 Hz), 7.45-7.40 (m, 3H), 7.08(m, 2H), 4.70-4.65 (m, 1H), 3.70-3.64 (m, 2H), 3.57 (d, 2H, J=6.8 Hz),3.37-3.32 (m, 2H), 2.04-1.94 (m, 3H), 1.79-1.71 (m, 2H), 0.95 (d, 6H,J=6.7 Hz).

Example 572.4-[4-(5-Chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-isopentyl-piperidine-1-carboxamide

The title compound was prepared in a manner similar in 65% yield. mp:185° C.; LC-MS: m/z=441 (M+1); 1H NMR (400 MHz, DMSO-d₆) δ: 8.09 (m,1H), 7.76 (d, 1H, J=1.3 Hz), 7.71 (m, 1H), 7.46 (m, 2H), 7.36 (d, 1H,J=9.2 Hz), 7.10 (m, 2H), 6.47 (m, 1H), 4.63-4.60 (m, 1H), 3.72-3.69 (m,2H), 3.16-3.01 (m, 4H), 1.94-1.91 (m, 2H), 1.60-1.47 (m, 3H), 1.33-1.28(m, 2H), 0.87 (d, 6H, J=6.6 Hz).

Example 573.4-[4-(5-Chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-ethoxy-piperidine-1-carboxamide

The title compound was prepared in a manner similar to the procedureused to prepare Example 7 in 28% yield. mp: 210° C.; LC-MS: m/z=443(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.66 (s, 1H), 8.09 (s, 1H), 7.76 (d,1H, J=1.2 Hz), 7.70 (d, 1H, J=9.2 Hz), 7.46 (m, 2H), 7.36 (d, 1H, J=9.2Hz), 7.10 (m, 2H), 4.66-4.62 (m, 1H), 3.77-3.72 (m, 2H), 3.66-3.60 (m,2H), 3.15-3.10 (m, 2H), 1.95 (m, 2H), 1.58-1.50 (m, 2H), 1.14-1.11 (m,3H).

Example 574.4-[4-(8-Methyl-7-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide

1,1′-Carbonyldiimidazole (0.082 g, 0.506 mmol), O-propylhydroxylamineHCl (0.05 g, 0.43 mmol) and DIPEA (0.11 mL, 0.63 mmol) in DCM (2.0 mL)and THF (0.5 mL) was stirred at rt for 2 h. In a separate vial,8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline (0.097 g, 0.305 mmol),DIPEA (0.11 mL, 0.63 mmol) and DCM (2.5 mL) were combined, added to thereaction and stirred at rt for 24 h. The reaction was diluted with EtOAcand washed with saturated NH₄Cl solution, water, saturated NaHCO₃solution, and then brine. The organic layer was dried over Na₂SO4,filtered and concentrated. The residue was triturated with ether, anddried under reduced pressure at 40° C. to yield a solid (65 mg, 51%) mp:75° C.; LC-MS: m/z=420 (M+1); 1H NMR (400 MHz, DMSO-d₆) δ: 9.65 (s, 1H),8.97 (m, 1H), 8.36 (m, 1H), 7.85 (d, 1H, J=8.4 Hz), 7.55 (m, 1H), 7.47(d, 1H, J=8.4 Hz), 7.37 (m, 2H), 7.10 (m, 2H), 4.65-4.61 (m, 1H),3.68-3.62 (m, 4H), 3.16-3.10 (m, 2H), 2.68 (s, 3H), 1.96 (m, 2H),1.59-1.50 (m, 4H), 0.92-0.88 (m, 3H).

Example 575.4-[4-(5-Chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carbohydroxamicacid

The title compound was prepared in a manner similar to the previousprocedure using hydroxylamine HCl in a 10% yield. mp: 232° C.; LC-MS:m/z=387 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.08 (s, 1H), 8.09 (s, 1H),7.99 (s, 1H), 7.76 (d, 1H, J=1.3 Hz), 7.70 (m, 1H), 7.46 (m, 2H), 7.36(d, 1H, J=9.2 Hz), 7.11 (m, 2H), 4.66-4.61 (m, 1H), 3.69-3.64 (m, 2H),3.16-3.09 (m, 2H), 1.96-1.92 (m, 2H), 1.57-1.50 (m, 2H).

Example 576.4-[4-(5-Chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-propoxy-piperidine-1-carboxamide

The title compound was prepared in a manner similar to the procedure in82% yield. LC-MS: m/z=429 (M+1); 1H NMR (400 MHz, DMSO-d₆) δ: 9.64 (s,1H), 8.09 (s, 1H), 7.76 (d, 1H, J=1.2 Hz), 7.70 (m, 1H), 7.46 (m, 2H),7.36 (d, 1H, J=9.2 Hz), 7.10 (m, 2H), 4.67-4.61 (m, 1H), 3.68-3.61 (m,4H), 3.15-3.10 (m, 2H), 1.97-1.92 (m, 2H), 1.58-1.50 (m, 4H).

Example 577.4-[4-(5-Chloroimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

The title compound was prepared in a similar manner similar usingisocyanato-(trimethyl)silane to give a 36% yield. mp: 204° C.; LC-MS:m/z=371 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.09 (s, 1H), 7.76 (d, 1H,J=1.3 Hz), 7.70 (m, 1H), 7.46 (m, 2H), 7.36 (d, 1H, J=9.2 Hz), 7.11 (m,2H), 5.97 (s, 2H), 4.65-4.59 (m, 1H), 3.73-3.67 (m, 2H), 3.15-3.09 (m,2H), 1.95-1.91 (m, 2H), 1.57-1.48 (m, 2H).

Example 578.N-Ethyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide

The title compound was prepared in a manner similar in 60% yield. mp:211° C.; LC-MS: m/z=390 (M+1); 1H NMR (400 MHz, DMSO-d₆) δ: 8.33 (d, 1H,J=5.8 Hz), 8.25 (d, 1H, J=8.8 Hz), 8.17 (d, 1H, J=1.7 Hz), 7.97 (m, 1H),7.79 (m, 2H), 7.69 (d, 1H, J=5.8 Hz), 7.14 (m, 2H), 6.51 (m, 1H),4.67-4.62 (m, 1H), 3.72-3.67 (m, 2H), 3.16-3.02 (m, 4H), 2.89 (s, 3H),1.95-1.92 (m, 2H), 1.57-1.48 (m, 2H), 1.03-0.99 (m, 3H).

Example 579.4-[4-(1-Methyl-6-isoquinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide

The title compound was prepared in a manner similar in 75% yield. mp:181° C.; LC-MS: m/z=404 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.34 (d, 1H,J=5.8 Hz), 8.25 (d, 1H, J=8.8 Hz), 8.17 (d, 1H, J=1.7 Hz), 7.97 (m, 1H),7.79 (m, 2H), 7.69 (d, 1H, J=5.8 Hz), 7.14 (m, 2H), 6.52 (m, 1H),4.67-4.62 (m, 1H), 3.73-3.68 (m, 2H), 3.16-3.10 (m, 2H), 3.01-2.96 (m,2H), 2.89 (s, 3H), 1.95 (m, 2H), 1.56-1.48 (m, 2H), 1.46-1.36 (m, 2H),0.85-0.81 (m, 3H).

Example 580.N-Isobutyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide

The title compound was prepared in a manner similar to the previousprocedure in 24% yield. mp: 157° C.; LC-MS: m/z=418 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ: 8.34 (d, 1H, J=5.8 Hz), 8.24 (d, 1H, J=8.8 Hz), 8.17(d, 1H, J=1.7 Hz), 7.97 (m, 1H), 7.79 (m, 2H), 7.69 (d, 1H, J=5.8 Hz),7.13 (m, 2H), 6.54 (m, 1H), 4.67-4.63 (m, 1H), 3.74-3.70 (m, 2H),3.17-3.10 (m, 2H), 2.89 (s, 3H), 2.86-2.83 (m, 2H), 1.95-1.92 (m, 2H),1.75-1.65 (m, 1H), 1.55-1.48 (m, 2H), 0.83 (d, 6H, J=6.7 Hz).

Example 581.4-[4-(1-Methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide

The title compound was prepared in a similar manner usingisocyanato(trimethyl)-silane in 64% yield. mp: 232° C.; LC-MS: m/z=362(M+1); 1H NMR (400 MHz, DMSO-d₆) δ: 8.34 (d, 1H, J=5.8 Hz), 8.25 (d, 1H,J=8.8 Hz), 8.18 (d, 1H, J=1.7 Hz), 7.97 (m, 1H), 7.80 (m, 2H), 7.70 (d,1H, J=5.8 Hz), 7.14 (m, 2H), 5.98 (s, 2H), 4.68-4.62 (m, 1H), 3.72-3.66(m, 2H), 3.17-3.11 (m, 2H), 2.89 (s, 3H), 1.96-1.91 (m, 2H), 1.57-1.49(m, 2H).

Example 582.N-(Cyclopropylmethyl)-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide

The title compound was prepared in a similar manner similar in 37%yield. mp: 188° C.; LC-MS: m/z=416 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ8.33 (d, 1H, J=5.8 Hz), 8.25 (d, 1H, J=8.8 Hz), 8.17 (d, 1H, J=1.7 Hz),7.98 (m, 1H), 7.79 (m, 2H), 7.69 (d, 1H, J=5.8 Hz), 7.14 (m, 2H), 6.60(m, 1H), 4.67-4.62 (m, 1H), 3.73-3.68 (m, 2H), 3.17-3.11 (m, 2H),2.93-2.89 (m, 5H), 1.95-1.92 (m, 2H), 1.57-1.49 (m, 2H), 0.98-0.88 (m,1H), 0.39-0.35 (m, 2H), 0.16-0.13 (m, 2H).

Example 583.N-Isopropoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide

The title compound was prepared in a similar manner similar in 55%yield. mp: 189° C.; HPLC 5.25 min. rt=2.223 min.; LC-MS: m/z=420 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ: 9.50 (s, 1H), 8.34 (d, 1H, J=5.8 Hz), 8.25(d, 1H, J=8.8 Hz), 8.17 (d, 1H, J=1.7 Hz), 7.97 (m, 1H), 7.79 (m, 2H),7.69 (d, 1H, J=5.8 Hz), 7.13 (m, 2H), 4.69-4.64 (m, 1H), 3.90-3.84 (m,1H), 3.67-3.61 (m, 2H), 3.17-3.11 (m, 2H), 2.89 (s, 3H), 1.97-1.92 (m,2H), 1.59-1.50 (m, 2H), 1.12 (d, 6H, J=6.2 Hz).

Example 584.4-[4-(1-Methyl-6-isoquinolyl)phenoxy]-N-propoxypiperidine-1-carboxamide

The title compound was prepared in a similar manner in 59% yield. mp:165° C.; LC-MS: m/z=420 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.64 (s,1H), 8.34 (d, 1H, J=5.8 Hz), 8.25 (d, 1H, J=8.8 Hz), 8.17 (d, 1H, J=1.6Hz), 7.97 (m, 1H), 7.80 (m, 2H), 7.69 (d, 1H, J=5.8 Hz), 7.14 (m, 2H),4.68-4.64 (m, 1H), 3.68-3.59 (m, 4H), 3.17-3.11 (m, 2H), 2.89 (s, 3H),1.99-1.93 (m, 2H), 1.59-1.50 (m, 4H), 0.92-0.88 (m, 3H).

Example 585.4-[4-(1-Methyl-6-isoquinolyl)phenoxy]piperidine-1-carbohydroxamic acid

The title compound was prepared in a similar manner using hydroxylamineHCl in 7% yield. mp: 185° C.; LC-MS: m/z=378 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ: 9.09 (br s, 1H), 8.55 (d, 1H, J=9.0 Hz), 8.50 (s, 1H), 8.46(d, 1H, J=6.4 Hz), 8.29 (m, 1H), 8.19 (m, 1H), 7.92 (m, 2H), 7.19 (m,2H), 4.72-4.68 (m, 1H), 3.68-3.62 (m, 2H), 3.18-3.13 (m, 5H), 1.96-1.93(m, 2H), 1.58-1.50 (m, 2H)

Example 586.N-Ethoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide

The title compound was prepared in a similar manner similar in 16%yield. mp: 208° C.; LC-MS: m/z=406 (M+1); 1H NMR (400 MHz, DMSO-d₆) δ:9.66 (s, 1H), 8.34 (d, 1H, J=5.8 Hz), 8.25 (d, 1H, J=8.8 Hz), 8.17 (d,1H, J=1.8 Hz), 7.97 (m, 1H), 7.80 (m, 2H), 7.69 (d, 1H, J=5.9 Hz), 7.14(m, 2H), 4.68-4.64 (m, 1H), 3.77-3.72 (m, 2H), 3.64-3.60 (m, 2H),3.17-3.11 (m, 2H), 2.89 (s, 3H), 1.96-1.92 (m, 2H), 1.59-1.50 (m, 2H),1.14-1.11 (m, 3H).

Example 587.N-Ethoxy-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide

The title compound was prepared in a similar manner in 59% yield. mp:152° C.; LC-MS: m/z=406 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.66 (s,1H), 8.73 (s, 1H), 8.19 (d, 1H, J=8.3 Hz), 8.04 (d, 1H, J=8.2 Hz),7.79-7.75 (m, 1H), 7.70-7.66 (m, 1H), 7.40 (d, 2H, J=8.6 Hz), 7.13 (d,2H, J=8.6 Hz), 4.67-4.63 (m, 1H), 3.78-3.73 (m, 2H), 3.66-3.63 (m, 2H),3.17-3.11 (m, 2H), 2.63 (s, 3H), 1.99-1.95 (m, 2H), 1.60-1.52 (m, 2H),1.15-1.11 (m, 3H) Example 588.N-Isopropoxy-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide

The title compound was prepared in a similar manner in 51% yield. mp:80° C.; LC-MS: m/z=420 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.51 (s, 1H),8.73 (s, 1H), 8.19 (d, 1H, J=7.7 Hz), 8.04 (d, 1H, J=8.3 Hz), 7.79-7.75(m, 1H), 7.70-7.66 (m, 1H), 7.40 (m, 2H), 7.13 (m, 2H), 4.67-4.63 (m,1H), 3.92-3.83 (m, 1H), 3.68-3.63 (m, 2H), 3.17-3.11 (m, 2H), 2.63 (s,3H), 1.99-1.95 (m, 2H), 1.60-1.52 (m, 2H), 1.12 (d, 6H, J=6.2 Hz).

Example 589.4-[4-(4-Methyl-3-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide

The title compound was prepared in a similar manner tin 61% yield. mp:75° C.; LC-MS: m/z=420 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.65 (s, 1H),8.73 (s, 1H), 8.18 (d, 1H, J=7.7 Hz), 8.04 (d, 1H, J=8.0 Hz), 7.79-7.75(m, 1H), 7.70-7.66 (m, 1H), 7.40 (m, 2H), 7.13 (m, 2H), 4.67-4.63 (m,1H), 3.68-3.62 (m, 4H), 3.17-3.10 (m, 2H), 2.63 (s, 3H), 1.99-1.95 (m,2H), 1.59-1.52 (m, 4H), 0.92-0.88 (m, 3H).

Example 590.N-Isobutyl-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide

The title compound was prepared in a similar manner in 54% yield. mp:153° C.; HPLC 5.25 min. rt=2.490 min.; LC-MS: m/z=418 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ: 8.73 (s, 1H), 8.19 (d, 1H, J=7.7 Hz), 8.04 (d, 1H,J=7.6 Hz), 7.79-7.75 (m, 1H), 7.70-7.66 (m, 1H), 7.40 (m, 2H), 7.13 (m,2H), 6.56-6.53 (m, 1H), 4.66-4.62 (m, 1H), 3.76-3.72 (m, 2H), 3.16-3.10(m, 2H), 2.87-2.84 (m, 2H), 2.63 (s, 3H), 1.95 (m, 2H), 1.74-1.67 (m,1H), 1.57-1.49 (m, 2H), 0.83 (d, 6H, J=6.7 Hz).

Example 591.4-[4-(4-Methyl-3-quinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide

The title compound was prepared in a similar manner in 64% yield. mp:171° C.; min; LC-MS: m/z=404 (M+1); 1H NMR (400 MHz, DMSO-d₆) δ 8.73 (s,1H), 8.19 (m, 1H), 8.04 (m, 1H), 7.79-7.74 (m, 1H), 7.70-7.66 (m, 1H),7.41-7.38 (m, 2H), 7.13 (m, 2H), 6.53 (m, 1H), 4.65-4.61 (m, 1H),3.75-3.70 (m, 2H), 3.15-3.09 (m, 2H), 3.01-2.96 (m, 2H), 2.63 (s, 3H),1.99-1.94 (m, 2H), 1.57-1.49 (m, 2H), 1.46-1.37 (m, 2H), 0.85-0.82 (m,3H).

Example 592.N-Ethyl-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

To a suspension of5-methyl-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl (0.060g, 0.158 mmol) in anhydrous DCM (3.0 mL) in a scintillation vial at RTunder N₂ was added DIPEA (0.0826 mL, 0.0612 g, 0.473 mmol) followed byisocyanatoethane (0.0187 mL, 0.0168 g, 0.237 mmol). The solution wasstirred at RT overnight. Saturated aqueous NaHCO₃ solution (3 mL) wasadded to the reaction. The vial was shaken and the layers separated. Theorganic layer was withdrawn via a syringe and loaded directly onto a 24g silica gel ISCO column (repeated with 2×2 mL of DCM). Flashchromatography on the ISCO (0 to 100% (33% 20:1:1 EtOH:NH₄OH:H₂O-67%EtOAc)-100 to 0% hexanes) yielded the desired compound as a white solid(0.041 g, 69%). Analysis: LCMS m/z=379 (M+1); ¹H NMR (400 MHz, DMSO-d₆)δ: 7.89 (s, 1H), 7.68 (d, J=1.3 Hz, 1H), 7.53 (d, J=9.0 Hz, 1H),7.37-7.31 (m, 2H), 7.20 (d, J=9.3 Hz, 1H), 7.11-7.05 (m, 2H), 6.50 (t,J=5.3 Hz, 1H), 4.60 (tt, J=8.1, 3.8 Hz, 1H), 3.76-3.65 (m, 2H),3.16-3.00 (m, 4H), 2.54 (s, 3H), 1.99-1.88 (m, 2H), 1.58-1.46 (m, 2H),1.02 (t, J=7.0 Hz, 3H).

Example 593.N-Isobutyl-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

To a suspension of5-methyl-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl (0.0600g, 0.158 mmol) in anhydrous DCM (3.0 mL) in a scintillation vial at RTunder N₂ was added DIPEA (0.0826 mL, 0.0612 g, 0.473 mmol) followed by1-isocyanato-2-methylpropane (0.0235 g, 0.237 mmol). The solutionstirred at RT overnight. Saturated aqueous NaHCO₃ solution (3 mL) wasadded to the reaction. The vial was shaken and the layers allowed toseparate. The organic layer was withdrawn via a syringe and needle andloaded directly onto a 24 g silica gel ISCO column (repeated with 2×2 mLof DCM). Flash chromatography on the ISCO (0 to 100% (33% 20:1:1EtOH:NH₄OH:H₂O-67% EtOAc)-100 to 0% hexanes) yielded the desiredcompound as a white solid (0.047 g, 73%). Analysis: LCMS m/z=407 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ: 7.89 (s, 1H), 7.68 (d, J=1.0 Hz, 1H), 7.53(d, J=9.0 Hz, 1H), 7.37-7.30 (m, 2H), 7.20 (d, J=9.3 Hz, 1H), 7.12-7.05(m, 2H), 6.54 (t, J=5.5 Hz, 1H), 4.61 (tt, J=8.2, 3.9 Hz, 1H), 3.78-3.67(m, 2H), 3.12 (ddd, J=13.2, 9.7, 3.0 Hz, 2H), 2.85 (dd, J=6.8, 5.8 Hz,2H), 2.54 (s, 3H), 1.99-1.88 (m, 2H), 1.70 (dquin, J=13.6, 6.8 Hz, 1H),1.58-1.45 (m, 2H), 0.83 (d, J=6.8 Hz, 6H).

Example 594.4-[4-(5-Methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-propyl-piperidine-1-carboxamide

To a suspension of5-methyl-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl (0.0600g, 0.158 mmol) in anhydrous DCM (3.0 mL) in a scintillation vial at RTunder N₂ was added DIPEA (0.0826 mL, 0.0612 g, 0.473 mmol) followed by1-isocyanatopropane (0.0222 mL, 0.0201 g, 0.237 mmol). The solution wasstirred at RT overnight. Saturated aqueous NaHCO₃ solution (3 mL) wasadded to the reaction. The vial was shaken and the layers allowed toseparate. The organic layer was withdrawn via a syringe and needle andloaded directly onto a 24 g silica gel ISCO column (repeated with 2×2 mLof DCM). Flash chromatography on the ISCO (0 to 100% (33% 20:1:1 EtOH:NH₄OH:H₂O-67% EtOAc)-100 to 0% hexanes) yielded the desired compound asa white solid (0.050 g, 81%). Analysis: LCMS m/z=393 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ: 7.89 (s, 1H), 7.68 (d, J=1.3 Hz, 1H), 7.53 (d, J=9.0Hz, 1H), 7.37-7.30 (m, 2H), 7.20 (d, J=9.0 Hz, 1H), 7.11-7.05 (m, 2H),6.51 (t, J=5.4 Hz, 1H), 4.65-4.55 (m, 1H), 3.77-3.66 (m, 2H), 3.11 (ddd,J=13.2, 9.6, 3.0 Hz, 2H), 3.03-2.94 (m, 2H), 2.54 (s, 3H), 1.99-1.88 (m,2H), 1.58-1.47 (m, 2H), 1.42 (sxt, J=7.3 Hz, 2H), 0.83 (t, J=7.4 Hz,3H).

Example 595.N-(Cyclopropylmethyl)-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]piperidine-1-carboxamide

To a suspension of5-methyl-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl (0.0600g, 0.158 mmol) in anhydrous DCM (3.0 mL) in a scintillation vial at RTunder N₂ was added DIPEA (0.0826 mL, 0.0612 g, 0.473 mmol) followed byisocyanatomethylcyclopropane (0.0230 g, 0.237 mmol). The solution wasstirred at RT overnight. Saturated aqueous NaHCO₃ solution (3 mL) wasadded to the reaction. The vial was shaken and the layers allowed toseparate. The organic layer was withdrawn via a syringe and needle andloaded directly onto a 24 g silica gel ISCO column (repeated with 2×2 mLof DCM). Flash chromatography on the ISCO (0 to 100% (33% 20:1:1 EtOH:NH₄OH:H₂O-67% EtOAc)-100 to 0% hexanes) yielded the desired compound asa white solid (0.053 g, 83%). Analysis: LCMS m/z=405 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ: 7.74 (s, 1H), 7.52 (d, J=1.0 Hz, 1H), 7.38 (d, J=9.3Hz, 1H), 7.22-7.16 (m, 2H), 7.05 (d, J=9.3 Hz, 1H), 6.97-6.90 (m, 2H),6.45 (t, J=5.6 Hz, 1H), 4.46 (tt, J=8.1, 3.8 Hz, 1H), 3.62-3.52 (m, 2H),2.97 (ddd, J=13.2, 9.5, 3.1 Hz, 2H), 2.76 (t, J=6.0 Hz, 2H), 2.39 (s,3H), 1.84-1.74 (m, J=9.3 Hz, 1H), 1.84-1.74 (m, 2H), 1.44-1.31 (m, 2H),0.84-0.73 (m, 1H), 0.25-0.18 (m, 2H), 0.03-0.04 (m, 2H).

Example 596.4-[4-(5-Methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-(3-pyridyl)piperidine-1-carboxamide

To a suspension of5-methyl-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl (0.0700g, 0.184 mmol) in anhydrous DCM (3.0 mL) in a scintillation vial at RTunder N₂ was added DIPEA (0.0963 mL, 0.0714 g, 0.552 mmol) followed by3-isocyanatopyridine (0.0442 g, 0.368 mmol). The solution was stirred atRT overnight. Saturated aqueous NaHCO₃ solution (3 mL) was added to thereaction. The vial was shaken and the layers allowed to separate. Theorganic layer was concentrated and the residue was purified bypreparative HPLC on the Gilson (5 to 40% MeCN-95 to 60% water (both with0.1% TFA) over 15 min.; Phenomenex Gemini 5 m NX-C₁₈ 100 Å 150×30 mmcolumn). The fractions were combined and partitioned between saturatedaqueous NaHCO₃ solution and DCM, then separated, dried with Na₂SO₄, andconcentrated to yield the desired compound as the free base, anoff-white solid (0.049 g, 62%). Analysis: LCMS m/z=428 (M+1); ¹H NMR(400 MHz, DMSO-d₆) δ: 8.76 (s, 1H), 8.65 (d, J=2.3 Hz, 1H), 8.15 (dd,J=4.8, 1.5 Hz, 1H), 7.91-7.86 (m, 2H), 7.68 (d, J=1.0 Hz, 1H), 7.53 (d,J=9.0 Hz, 1H), 7.38-7.33 (m, 2H), 7.27 (dd, J=8.7, 4.4 Hz, 1H), 7.21 (d,J=9.3 Hz, 1H), 7.14-7.09 (m, 2H), 4.69 (tt, J=8.0, 4.0 Hz, 1H),3.93-3.81 (m, 2H), 3.39-3.36 (m, 1H), 2.55 (s, 3H), 2.04 (ddd, J=9.4,6.0, 3.1 Hz, 2H), 1.70-1.59 (m, 2H).

Example 597.N-(2-Methoxyethyl)-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

To a suspension of5-methyl-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl (0.0600g, 0.158 mmol) in anhydrous DCM (3.0 mL) in a scintillation vial at RTunder N₂ was added DIPEA (0.0826 mL, 0.0612 g, 0.473 mmol) followed by1-isocyanato-2-methoxyethane (0.0239 g, 0.237 mmol). The solution wasstirred at RT overnight. Saturated aqueous NaHCO₃ solution (3 mL) wasadded to the reaction. The vial was shaken and the layers allowed toseparate. The organic layer was withdrawn via a syringe and needle andloaded directly onto a 24 g silica gel ISCO column (repeated with 2×2 mLof DCM). Flash chromatography on the ISCO (0 to 100% (33% 20:1:1EtOH:NH₄OH:H₂O-67% EtOAc)-100 to 0% hexanes) yielded the desiredcompound as an off-white solid (0.062 g, 96%). Analysis: LCMS m/z=409(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.89 (s, 1H), 7.67 (d, J=1.3 Hz,1H), 7.53 (d, J=9.3 Hz, 1H), 7.36-7.31 (m, 2H), 7.20 (d, J=9.0 Hz, 1H),7.11-7.06 (m, 2H), 6.58 (t, J=5.5 Hz, 1H), 4.60 (tt, J=8.1, 3.9 Hz, 1H),3.76-3.65 (m, 2H), 3.36-3.33 (m, 2H), 3.24 (s, 3H), 3.22-3.08 (m, 4H),2.54 (s, 3H), 1.98-1.89 (m, 2H), 1.58-1.46 (m, 2H).

Example 598.[4-[4-(5-Methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-1-piperidyl]-(4-methylpiperazin-1-yl)methanone

Step 1. (4-Nitrophenyl)4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxylate

To a solution of 4-nitrophenyl chloroformate (0.233 g, 1.16 mmol) inanhydrous DCM (2.0 mL) in a scintillation vial in a bath of cool tapwater under N₂ was added a suspension of5-methyl-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl (0.400g, 1.05 mmol) and TEA (0.484 mL, 0.351 g, 3.47 mmol) in anhydrous DCM(2.0 mL+2×1.0 mL rinse). The reaction stirred for 60 min. The suspensionwas partitioned between DCM and water and separated. The aqueous layerwas re-extracted with DCM. The organic layers were combined and washedwith brine, then dried over Na₂SO₄, filtered, and concentrated. Silicagel chromatography on the ISCO (0 to 100% (20% MeOH-80% EtOAc)-100 to 0%hexanes; 40 g column) yielded the desired compounds as a yellowish foam(0.330 g, 66%). Analysis: LCMS m/z=473 (M+1); ¹H NMR (400 MHz, DCCl₃) δ:8.30-8.24 (m, 2H), 7.75 (d, J=1.3 Hz, 1H), 7.62 (d, J=9.3 Hz, 1H), 7.55(s, 1H), 7.35-7.27 (m, 4H), 7.21 (d, J=9.0 Hz, 1H), 7.05-7.00 (m, 2H),4.67 (tt, J=6.3, 3.3 Hz, 1H), 3.95-3.63 (m, 4H), 2.57 (s, 3H), 2.12-1.94(m, 5H).

Step 2.[4-[4-(5-Methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-1-piperidyl]-(4-methylpiperazin-1-yl)methanone

A mixture of (4-nitrophenyl)4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-piperidine-1-carboxylate(0.060 g, 0.13 mmol), 1-methylpiperazine (0.070 mL, 0.064 g, 0.63 mmol),and K₂CO₃ (0.026 g, 0.19 mmol) in anhydrous DMF (2.0 mL) in a smallmicrowave vial under Ar was heated in the microwave at 150° C. for 15min. The mixture was partitioned between DCM and saturated aqueousNaHCO₃ solution and separated. The aqueous layer was re-extracted with40 mL of DCM. The organic layers were combined and washed with water,then brine, then dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by preparative HPLC on the Gilson (5 to 40% MeCN-95to 60% water (both with 0.1% TFA) over 15 min.; Phenomenex Gemini 5 mNX-C₁₈ 100 Å 150×30 mm column). The good fractions were combined andpartitioned between saturated aqueous NaHCO₃ solution and DCM, thenseparated, dried with Na₂SO₄, and concentrated to yield the desiredcompound as the free base, a yellow solid. Analysis: LCMS m/z=434 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ: 7.89 (s, 1H), 7.67 (d, J=1.3 Hz, 1H), 7.53(d, J=9.0 Hz, 1H), 7.37-7.31 (m, 2H), 7.20 (d, J=9.3 Hz, 1H), 7.11-7.05(m, 2H), 4.62 (tt, J=8.0, 3.8 Hz, 1H), 3.51-3.41 (m, 2H), 3.20-3.11 (m,4H), 3.06 (ddd, J=13.0, 9.3, 3.0 Hz, 2H), 2.54 (s, 3H), 2.28 (t, J=4.8Hz, 4H), 2.17 (s, 3H), 2.02-1.92 (m, 2H), 1.67-1.55 (m, 2H).

Example 599.N,N-Dimethyl-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

A mixture of (4-nitrophenyl)4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)-phenoxy]piperidine-1-carboxylate(0.060 g, 0.13 mmol), O-isopropylhydroxylamine HCl (0.043 g, 0.38 mmol),and K₂CO₃ (0.079 g, 0.57 mmol) in anhydrous DMF (2.0 mL) in a smallmicrowave vial under Ar was heated in the microwave at 150° C. for 15min. LC-MS showed primarily unreacted starting material and ˜22% of theN,N-dimethylurea product derived from high-temperature decomposition ofthe DMF. The reaction was heated an additional 45 min. at 150° C., andLCMS showed almost exclusively the unintended N,N-dimethylurea product.The mixture was partitioned between DCM and saturated aqueous NaHCO₃solution and separated. The aqueous layer was re-extracted with 40 mL ofDCM. The organic layers were combined and washed with water, then brine,then dried over Na₂SO₄, filtered, and concentrated. Silica gelchromatography on the ISCO (0 to 100% (33% 20:1:1 EtOH:NH₄OH:H₂O-67%EtOAc)-100 to 0% hexanes) yielded the compound as a tan solid (0.034 g,71%). Analysis: LCMS m/z=379 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.89(s, 1H), 7.68 (d, J=1.0 Hz, 1H), 7.53 (d, J=9.3 Hz, 1H), 7.37-7.31 (m,2H), 7.21 (d, J=9.0 Hz, 1H), 7.11-7.06 (m, 2H), 4.62 (tt, J=8.1, 3.9 Hz,1H), 3.47-3.39 (m, 2H), 3.02 (ddd, J=13.1, 9.4, 3.1 Hz, 2H), 2.75 (s,6H), 2.54 (s, 3H), 2.04-1.93 (m, 2H), 1.68-1.56 (m, 2H).

Example 600.N-Isopropoxy-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

Step 1

To a solution of triphosgene (0.049 g, 0.17 mmol) in anhydrous DCM (2.0mL) in a large scintillation vial at 0° C. under N₂ was added a solutionof 5-methyl-6-[4-(4-piperidyloxy)-phenyl]imidazo[1,2-a]pyridine 2HCl(0.060 g, 0.16 mmol) and TEA (0.088 mL, 0.064 g, 0.63 mmol) in anhydrousDCM (1.5 mL+2×0.5 mL rinses) dropwise. The yellowish solution stirred at0° C. for about 60 min. The reaction was concentrated to yield ayellowish solid.

Step 2

In a separate vial, O-isopropylhydroxylamine HCl (0.053 g, 0.47 mmol)was suspended in anhydrous 1,2-dichloroethane (1.5 mL), and DIPEA (0.12mL, 0.092 g, 0.71 mmol) was added. The resulting solution was addeddropwise to the vial containing the carbamoyl chloride, which was thenheated to 70° C. before the heat was turned off and the reaction stirredat RT overnight. The mixture was partitioned between EtOAc and saturatedaqueous NaHCO₃ solution and separated. The organic layer was washed withwater, then brine, then dried over Na₂SO₄, filtered, and concentrated.Silica gel chromatography on the ISCO (0 to 100% (33% 20:1:1EtOH:NH₄OH:H₂O-67% EtOAc)-100 to 0% hexanes; 24 g column) yielded thedesired compound as an off-white solid (0.034 g, 53%). Analysis: LCMSm/z=409 (M+1); ¹H NMR (400 MHz, DMSO-d6) δ: 9.50 (s, 1H), 7.89 (s, 1H),7.68 (d, J=1.3 Hz, 1H), 7.53 (d, J=9.3 Hz, 1H), 7.37-7.30 (m, 2H), 7.20(d, J=9.3 Hz, 1H), 7.11-7.05 (m, 2H), 4.62 (tt, J=8.0, 3.8 Hz, 1H), 3.87(spt, J=6.2 Hz, 1H), 3.70-3.59 (m, 2H), 3.13 (ddd, J=13.1, 9.5, 3.3 Hz,2H), 2.54 (s, 3H), 2.00-1.89 (m, 2H), 2.00-1.89 (m, 2H), 1.60-1.48 (m,2H), 1.12 (d, J=6.3 Hz, 6H).

Example 601.N-Isobutoxy-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

Step 1

To a solution of triphosgene (0.049 g, 0.17 mmol) in anhydrous DCM (2.0mL) in a large scintillation vial at 0° C. under N₂ was added a solutionof 5-methyl-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl(0.060 g, 0.16 mmol) and TEA (0.088 mL, 0.064 g, 0.63 mmol) in anhydrousDCM (1.5 mL+2×0.5 mL rinses) dropwise. The yellowish solution stirred at0° C. for about 60 min. The reaction was concentrated to yield ayellowish solid.

Step 2

In a separate vial, O-isobutylhydroxylamine HCl (0.059 g, 0.47 mmol) wassuspended in anhydrous 1,2-dichloroethane (1.5 mL), and DIPEA (0.12 mL,0.092 g, 0.71 mmol) was added. The resulting solution was added dropwiseto the vial containing the carbamoyl chloride, which was then heated to80° C. for several hours. The mixture was partitioned between EtOAc andsaturated aqueous NaHCO₃ solution and separated. The organic layer waswashed with water, then brine, then dried over Na₂SO₄, filtered, andconcentrated. Silica gel chromatography on the ISCO (0 to 100% (33%20:1:1 EtOH: NH₄OH:H₂O-67% EtOAc)-100 to 0% hexanes; 24 g column)yielded the desired compound as an off-white solid (0.030 g, 45%).Analysis: LCMS m/z=423 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.64 (s, 1H),7.89 (s, 1H), 7.68 (d, J=1.3 Hz, 1H), 7.53 (d, J=9.3 Hz, 1H), 7.37-7.30(m, 2H), 7.20 (d, J=9.3 Hz, 1H), 7.11-7.05 (m, 2H), 4.66-4.57 (m, J=8.1,4.1, 4.1 Hz, 1H), 3.68-3.57 (m, 2H), 3.49 (d, J=6.8 Hz, 2H), 3.18-3.08(m, 2H), 2.54 (s, 3H), 1.99-1.90 (m, 2H), 1.90-1.80 (m, 1H), 1.60-1.48(m, 2H), 0.89 (d, J=6.8 Hz, 6H).

Example 602. Isobutyl4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxylate

To a solution of isobutyl carbonochloridate (0.031 mL, 0.032 g, 0.24mmol) in anhydrous DCM (1.5 mL) in a large scintillation vial at 0° C.under N₂ was added a solution of5-methyl-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl (0.060g, 0.16 mmol) and DIPEA (0.11 mL, 0.082 g, 0.63 mmol) in anhydrous DCM(1.0 mL+2×0.5 mL rinse) dropwise. The reaction was stirred at 0° C. for90 min. The reaction was quenched by adding 3 mL of saturated aqueousNaHCO₃ solution, then partitioned between EtOAc and additional saturatedaqueous NaHCO₃ solution and separated. The organic layer was washed withwater, then brine, then dried over Na₂SO₄, filtered, and concentrated.Silica gel chromatography on the ISCO (0 to 80% (33% 20:1:1 EtOH:NH₄OH:H₂O-67% EtOAc)-100 to 20% hexanes; 24 g column) yielded thedesired compound as an off-white solid (0.047 g, 73%). Analysis: LCMSm/z=408 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.89 (s, 1H), 7.68 (d, J=1.3Hz, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.37-7.31 (m, 2H), 7.21 (d, J=9.3 Hz,1H), 7.12-7.06 (m, 2H), 4.65 (tt, J=7.9, 3.7 Hz, 1H), 3.80 (d, J=6.5 Hz,2H), 3.78-3.69 (m, 2H), 3.31-3.20 (m, 2H), 2.54 (s, 3H), 2.02-1.93 (m,2H), 1.88 (dquin, J=13.3, 6.7 Hz, 1H), 1.59 (dtd, J=12.8, 8.6, 3.9 Hz,2H), 0.90 (d, J=6.8 Hz, 6H).

Example 603.N-Isopropyl-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

To a suspension of5-methyl-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl (0.0600g, 0.158 mmol) in anhydrous DCM (3.0 mL) in a scintillation vial at RTunder N₂ was added DIPEA (0.0826 mL, 0.0612 g, 0.473 mmol) followed by2-isocyanatopropane (0.0232 mL, 0.0201 g, 0.237 mmol). The solutionstirred at RT overnight. Saturated aqueous NaHCO₃ solution (3 mL) wasadded to the reaction. The vial was shaken and the layers allowed toseparate. The organic layer was withdrawn via a syringe and needle andloaded directly onto a 24 g silica gel ISCO column (repeated with 2×2 mLof DCM). Flash chromatography on the ISCO (0 to 100% (33% 20:1:1 EtOH:NH₄OH:H₂O-67% EtOAc)-100 to 0% hexanes) yielded the desired compound asa white solid (0.051 g, 82%). Analysis: LCMS m/z=393 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ: 7.89 (s, 1H), 7.68 (d, J=1.3 Hz, 1H), 7.53 (d, J=9.3Hz, 1H), 7.37-7.31 (m, 2H), 7.21 (d, J=9.3 Hz, 1H), 7.12-7.05 (m, 2H),6.21 (d, J=7.8 Hz, 1H), 4.65-4.55 (m, 1H), 3.83-3.66 (m, 3H), 3.10 (ddd,J=13.1, 9.6, 3.1 Hz, 2H), 2.54 (s, 3H), 1.98-1.88 (m, 2H), 1.58-1.45 (m,2H), 1.06 (d, J=6.5 Hz, 6H).

Example 604.4-[4-(5-Methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-(1-methylpyrazol-4-yl)piperidine-1-carboxamide

To a suspension of5-methyl-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl (0.0600g, 0.158 mmol) in anhydrous DCM (3.0 mL) in a scintillation vial at RTunder N₂ was added DIPEA (0.0826 mL, 0.0612 g, 0.473 mmol) followed by4-isocyanato-1-methyl-pyrazole (0.0291 g, 0.237 mmol). The solutionstirred at RT overnight. The mixture was partitioned between EtOAc andsaturated aqueous NaHCO₃ solution and separated. The organic layer waswashed with water, then brine, then dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by preparative HPLC on the Gilson(5 to 50% MeCN-95 to 50% water (both with 0.1% TFA) over 15 min.;Phenomenex Gemini 5 m NX-C₁₈ 100 Å 150×30 mm column). The good fractionswere combined and partitioned between saturated aqueous NaHCO₃ solutionand DCM, then separated, dried with Na₂SO₄, and concentrated to yieldthe desired compound as the free base, an off-white solid (0.048 g,71%). Analysis: LCMS m/z=431 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.55(s, 1H), 7.90 (s, 1H), 7.68 (s, 1H), 7.67 (s, 1H), 7.53 (d, J=9.0 Hz,1H), 7.38-7.31 (m, 3H), 7.21 (d, J=9.3 Hz, 1H), 7.13-7.07 (m, 2H),4.70-4.61 (m, J=8.0, 4.2, 4.2 Hz, 1H), 3.85-3.77 (m, 2H), 3.75 (s, 3H),3.25 (ddd, J=13.2, 9.6, 3.0 Hz, 2H), 2.55 (s, 3H), 2.04-1.95 (m, 2H),1.64-1.54 (m, 2H).

Example 605. tert-Butyl4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxylate

Triphenylphosphine (0.702 g, 2.68 mmol) and palladium(II) acetate (0.150g, 0.669 mmol) were placed in a pressure flask, then dissolved in1,4-dioxane (27 mL). Nitrogen gas was bubbled through the solution forseveral minutes, then the flask was capped and stirred at RT for 30 min.While again bubbling N₂ through the mixture, tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]piperidine-1-carboxylate(5.40 g, 13.4 mmol), 6-bromo-5-methyl-imidazo[1,2-a]pyridine (2.97 g,14.1 mmol), DMF (38 mL), and 1 M aqueous Na₂CO₃ solution (40.2 mmol)were added, and the flask was capped and heated to 80° C. for abouteight hours before the heat was turned off and the reaction was stirredat RT overnight. The mixture was concentrated, then partitioned betweenEtOAc and saturated aqueous NaHCO₃ solution and separated. The aqueouslayer was re-extracted with 100 mL of EtOAc. The organic layers werecombined and washed with water (2×), then brine, then dried over Na₂SO₄,filtered, and concentrated. Silica gel chromatography on the ISCO (0 to100% (20% 20:1:1 EtOH:NH₄OH:H₂O-80% EtOAc)-100 to 0% hexanes; 120 gcolumn) yielded the desired compound as a white solid. Analysis: LCMSm/z=408 (M+1); ¹H NMR (400 MHz, DMSO-d6) δ: 7.89 (s, 1H), 7.68 (d, J=1.0Hz, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.37-7.31 (m, 2H), 7.20 (d, J=9.3 Hz,1H), 7.12-7.06 (m, 2H), 4.63 (tt, J=8.0, 3.7 Hz, 1H), 3.74-3.65 (m, 2H),3.26-3.14 (m, J=9.5, 9.5 Hz, 2H), 2.54 (s, 3H), 2.00-1.90 (m, 2H),1.61-1.50 (m, 2H), 1.41 (s, 9H).

Example 606.4-[4-(5-Methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-(2,2,2-trifluoro-ethyl)piperidine-1-carboxamide

To a solution of 1,1′-carbonyldiimidazole (0.0426 g, 0.263 mmol) in a4:1 mixture of anhydrous DCM (1.60 mL) and THF (0.40 mL) in a largescintillation vial at RT under N₂ was added 2,2,2-trifluoroethanamine(0.0125 mL, 0.0173 g, 0.175 mmol). The solution stirred at RT for abouttwo hours before adding a solution of5-methyl-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl (0.0832g, 0.219 mmol) and DIPEA (0.0916 mL, 0.0679 g, 0.525 mmol) in anhydrousDCM (1.0 mL+2×0.5 mL rinses) dropwise. The reaction was stirred at RTfor 72 hours. The mixture was partitioned between EtOAc and saturatedaqueous NaHCO₃ solution and separated. The organic layer was washed withwater, then brine, then dried over Na₂SO₄, filtered, and concentrated.The residue was purified by preparative HPLC on the Gilson (10 to 50%MeCN-90 to 50% water (both with 0.1% TFA) over 15 min.; PhenomenexGemini 5 m NX-C₁₈ 100 Å 150×30 mm column). The fractions were combinedand partitioned between saturated aqueous NaHCO₃ solution and DCM, thenseparated, dried with Na₂SO₄, and concentrated to yield the desiredcompound as the free base, an off-white solid (0.038 g, 50%). Analysis:LCMS m/z=433 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (s, 1H), 7.68 (s,1H), 7.53 (d, J=9.3 Hz, 1H), 7.37-7.31 (m, 2H), 7.24-7.16 (m, 2H),7.12-7.06 (m, 2H), 4.69-4.59 (m, J=8.0, 4.2, 4.2 Hz, 1H), 3.84 (qd,J=9.8, 6.3 Hz, 2H), 3.78-3.70 (m, 2H), 3.20 (ddd, J=13.2, 9.6, 3.0 Hz,2H), 2.54 (s, 3H), 2.01-1.91 (m, 2H), 1.60-1.49 (m, 2H). ¹⁹F NMR (377MHz, DMSO-d6) δ −71.22 (s, 1F).

Example 607.4-[4-(5-Methylimidazo[1,2-a]pyridin-6-yl)phenoxy]-N-propoxy-piperidine-1-carboxamide

To a solution of 1,1′-carbonyldiimidazole (0.051 g, 0.31 mmol) in a 4:1mixture of anhydrous DCM (1.60 mL) and THF (0.40 mL) in a largescintillation vial at RT under N₂ was added a solution ofO-propylhydroxylamine HCl (0.032 g, 0.29 mmol) and DIPEA (0.058 mL,0.043 g, 0.34 mmol) in the 4:1 solvent mixture (1.0 mL+2×0.5 mL rinses)dropwise. The solution stirred at RT for about two hours before adding asolution of 5-methyl-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine2HCl (0.085 g, 0.22 mmol) and DIPEA (0.058 mL, 0.043 g, 0.34 mmol) inanhydrous DCM (1.0 mL+2×0.5 mL rinses) dropwise. The reaction wasstirred at RT for two hours. The mixture was partitioned between EtOAcand saturated aqueous NaHCO₃ solution and separated. The organic layerwas washed with water, then brine, then dried over Na₂SO₄, filtered, andconcentrated. Silica gel chromatography on the ISCO (0 to 100% (33%20:1:1 EtOH: NH₄OH:H₂O-67% EtOAc)-100 to 0% hexanes; 24 g column)yielded an off-white solid. The compound was partitioned between DCM andsaturated aqueous NH₄Cl solution and separated. The aqueous layer wasre-extracted with DCM. The organic layers were combined and washed withwater, saturated aqueous NaHCO₃ solution, and brine, then dried overNa₂SO₄, filtered, and concentrated to yield the desired compound as anoff-white solid (0.058 g, 64%). Analysis: LCMS m/z=409 (M+1); ¹H NMR(400 MHz, DMSO-d₆) δ: 9.64 (s, 1H), 7.89 (s, 1H), 7.68 (d, J=1.3 Hz,1H), 7.53 (d, J=9.3 Hz, 1H), 7.37-7.31 (m, 2H), 7.20 (d, J=9.0 Hz, 1H),7.12-7.05 (m, 2H), 4.62 (tt, J=7.9, 3.7 Hz, 1H), 3.69-3.59 (m, 4H), 3.13(ddd, J=13.2, 9.5, 3.1 Hz, 2H), 2.54 (s, 3H), 2.00-1.89 (m, 2H),1.60-1.48 (m, 4H), 0.90 (t, J=7.5 Hz, 3H).

Example 608.N-Ethoxy-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

To a solution of 1,1′-carbonyldiimidazole (0.051 g, 0.32 mmol) in a 4:1mixture of anhydrous DCM (2.00 mL) and THF (0.50 mL) in a largescintillation vial at RT under N₂ was added DIPEA (0.073 mL, 0.054 g,0.42 mmol) followed by O-ethylhydroxylamine HCl (0.029 g, 0.29 mmol).The mixture was stirred at RT for about two hours before adding asolution of 5-methyl-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine2HCl (0.080 g, 0.21 mmol) and DIPEA (0.073 mL, 0.054 g, 0.42 mmol) inanhydrous DCM (1.0 mL+2×0.5 mL rinses) dropwise. The resulting mixturewas stirred at RT overnight. The mixture was partitioned between EtOAcand saturated aqueous NH₄Cl solution and separated. The organic layerwas washed with 15 mL of water, saturated aqueous NaHCO₃ solution, andbrine, then dried over Na₂SO₄, filtered, and concentrated. Silica gelchromatography on the ISCO (0 to 100% (33% 20:1:1 EtOH:NH₄OH:H₂O-67%EtOAc)-100 to 0% hexanes; 24 g column) yielded the desired compound as awhite solid (0.073 g, 88%). Analysis: LCMS m/z=395 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ: 9.66 (s, 1H), 7.89 (s, 1H), 7.68 (d, J=1.3 Hz, 1H),7.53 (d, J=9.0 Hz, 1H), 7.37-7.31 (m, 2H), 7.20 (d, J=9.3 Hz, 1H),7.11-7.06 (m, 2H), 4.67-4.57 (m, J=8.0, 4.3, 4.3 Hz, 1H), 3.75 (q, J=7.0Hz, 2H), 3.68-3.58 (m, 2H), 3.13 (ddd, J=13.2, 9.5, 3.1 Hz, 2H), 2.54(s, 3H), 2.00-1.89 (m, 2H), 1.60-1.48 (m, 2H), 1.13 (t, J=7.0 Hz, 3H).

Example 609.2-Amino-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]ethanone, 2HCl

Step 1

To a suspension of 2-(tert-butoxycarbonylamino)acetic acid (0.053 g,0.30 mmol) and HATU (0.11 g, 0.30 mmol) in anhydrous DCM (2.0 mL) in alarge scintillation vial at RT under N₂ was added DIPEA (0.18 mL, 0.13g, 1.0 mmol). The mixture stirred for 20 min. before adding8-methyl-7-[4-(4-piperidyloxy)phenyl]quinolone (0.080 g, 0.25 mmol) andstirring at RT overnight. The mixture was partitioned between EtOAc andsaturated aqueous NH₄Cl solution and separated. The organic layer waswashed with water, saturated aqueous NaHCO₃ solution, and brine, thendried over Na₂SO₄, filtered, and concentrated. Silica gel chromatographyon the ISCO (0 to 100% EtOAc-100 to 0% hexanes; 24 g column) yieldedtert-butylN-[2-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-2-oxo-ethyl]carbamateas an off-white foam.

Step 2

To a solution of tert-butylN-[2-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-2-oxo-ethyl]carbamate(0.120 g, 0.252 mmol) in anhydrous EtOAc (3.0 mL) in a small RBF at RTunder N₂ was added HCl (4 mol/L) in 1,4-dioxane (3.0 mL, 12 mmol)dropwise. A yellowish precipitate formed immediately. The reactionstirred at RT for about two hours. The reaction was concentrated. Theresidue was partitioned between EtOAc and saturated aqueous NH₄Clsolution and separated. The organic layer was washed with water,saturated aqueous NaHCO₃ solution, and brine, then dried over Na₂SO₄,filtered and concentrated to yield a yellowish oil. The material wastransferred to a vial, then dissolved in 0.5 mL of DCM before adding0.250 mL of the 4.0 M HCl-dioxane solution while stirring. A precipitateformed immediately. The reaction was concentrated and dried under vacuumto yield the desired product as the dihydrochloride salt, a yellow solid(0.090 g, 80%). Analysis: LCMS m/z=376 (M+1); ¹H NMR (400 MHz, DMSO-d⁶)δ: 9.06 (dd, J=4.3, 1.5 Hz, 1H), 8.69-8.51 (m, 1H), 8.14 (t, J=5.0 Hz,3H), 7.98 (d, J=8.5 Hz, 1H), 7.72 (dd, J=7.7, 4.4 Hz, 1H), 7.59 (d,J=8.3 Hz, 1H), 7.41 (d, J=8.8 Hz, 2H), 7.14 (d, J=8.8 Hz, 2H), 4.76 (tt,J=7.6, 3.6 Hz, 1H), 3.92 (d, J=5.8 Hz, 3H), 3.42-3.31 (m, 3H), 2.71 (s,3H), 2.10-1.95 (m, 1H), 2.10-1.95 (m, 2H), 1.77-1.66 (m, 1H), 1.66-1.54(m, J=12.6, 8.5, 4.1, 4.1 Hz, 1H).

Example 610.(2R)-2-Amino-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]propan-1-one,2HCl

Step 1

To a suspension of (2R)-2-(tert-butoxycarbonylamino)propanoic acid(0.057 g, 0.30 mmol) and HATU (0.11 g, 0.30 mmol) in anhydrous DCM (2.00mL) in a large scintillation vial at RT under N₂ was added DIPEA (0.18mL, 0.13 g, 1.0 mmol). The mixture stirred for ˜20 min. before adding8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline (0.080 g, 0.25 mmol) andstirring at RT overnight. The mixture was partitioned between EtOAc andsaturated aqueous NH₄Cl solution and separated. The organic layer waswashed with water, saturated aqueous NaHCO₃ solution, and brine, thendried over Na₂SO₄, filtered, and concentrated to yield a cloudy,colorless oil. Silica gel chromatography on the ISCO (0 to 100%EtOAc-100 to 0% hexanes; 24 g column) yielded tert-butylN-[(1R)-1-methyl-2-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-2-oxo-ethyl]carbamateas a white foam.

Step 2

To a solution of tert-butylN-[(1R)-1-methyl-2-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-2-oxo-ethyl]carbamatein anhydrous EtOAc (5.0 mL) in a small RBF at RT under N₂ was added HCl(4 mol/L) in 1,4-dioxane (5.0 mL, 20 mmol) dropwise. The mixture stirredfor several hours before the reaction was concentrated to yield thedesired product as the dihydrochloride salt, a yellow solid (0.116 g,100%). Analysis: LCMS m/z=390 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.08(dd, J=4.4, 1.1 Hz, 1H), 8.67 (d, J=6.3 Hz, 1H), 8.18 (d, J=4.0 Hz, 3H),8.01 (d, J=8.5 Hz, 1H), 7.75 (dd, J=7.8, 4.5 Hz, 1H), 7.61 (d, J=8.5 Hz,1H), 7.41 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 4.84-4.69 (m, 1H),4.47-4.35 (m, 1H), 4.22-4.09 (m, 1H), 4.06-3.97 (m, J=12.3 Hz, 1H),3.52-3.44 (m, 5H), 3.34-3.25 (m, 1H), 2.71 (s, 3H), 2.11-1.92 (m, 3H),1.77-1.53 (m, 2H), 1.34 (dd, J=6.8, 2.3 Hz, 3H).

Example 611.N-Methoxy-4-[4-(5-methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

To a solution of 1,1′-carbonyldiimidazole (0.051 g, 0.32 mmol) in a 4:1mixture of anhydrous DCM (2.00 mL) and THF (0.50 mL) in a largescintillation vial at RT under N₂ was added DIPEA (0.073 mL, 0.054 g,0.42 mmol) followed by O-methylhydroxylamine HCl (0.025 g, 0.29 mmol).The solution stirred at RT for about two hours before adding additionalDIPEA (0.073 mL, 0.054 g, 0.42 mmol) and5-methyl-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl (0.080g, 0.21 mmol). The resulting mixture was stirred at RT overnight. Themixture was partitioned between EtOAc and saturated aqueous NH₄Clsolution and separated. The organic layer was washed with water,saturated aqueous NaHCO₃ solution, and brine, then dried over Na₂SO₄,filtered, and concentrated. Silica gel chromatography on the ISCO (0 to100% (33% 20:1:1 EtOH: NH₄OH:H₂O-67% EtOAc)-100 to 0% hexanes; 24 gcolumn) yielded the desired product as a white solid (0.061 g, 76%).Analysis: LCMS m/z=381 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.74 (s, 1H),7.89 (s, 1H), 7.68 (d, J=1.3 Hz, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.37-7.30(m, 2H), 7.20 (d, J=9.0 Hz, 1H), 7.11-7.05 (m, 2H), 4.62 (tt, J=8.0, 3.7Hz, 1H), 3.68-3.57 (m, 2H), 3.54 (s, 3H), 3.18-3.08 (m, 2H), 2.54 (s,3H), 2.00-1.89 (m, 2H), 1.61-1.49 (m, 2H).

Example 612.(2S)-2-Amino-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]propan-1-one2HCl

Step 1

To a suspension of (2S)-2-(tert-butoxycarbonylamino)propanoic acid(0.057 g, 0.30 mmol) and HATU (0.11 g, 0.30 mmol) in anhydrous DCM in ascintillation vial at RT under N₂ was added DIPEA (0.18 mL, 0.13 g, 1.0mmol). The mixture stirred for ˜20 min. before adding8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline (0.080 g, 0.25 mmol) andstirring at RT overnight. The mixture was partitioned between EtOAc andsaturated aqueous NH₄Cl solution and separated. The organic layer waswashed with water, saturated aqueous NaHCO₃ solution, and brine, thendried over Na₂SO₄, filtered, and concentrated. Silica gel chromatographyon the ISCO (0 to 100% EtOAc-100 to 0% hexanes; 24 g column) yieldedtert-butylN-[(1S)-1-methyl-2-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-2-oxo-ethyl]carbamateas a white foam.

Step 2

To a solution of tert-butylN-[(1S)-1-methyl-2-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-2-oxo-ethyl]carbamatein anhydrous EtOAc (5.0 mL) in a small RBF at RT under N₂ was added HCl(4 mol/L) in 1,4-dioxane solution (5.0 mL, 20 mmol) dropwise. Themixture stirred for several hours before the reaction was concentratedto yield the desired product as the dihydrochloride salt, a yellow solid(0.113 g, 97%). Analysis: LCMS m/z=390 (M+1); ¹H NMR (400 MHz, DMSO-d₆)δ: 9.08 (dd, J=4.4, 1.4 Hz, 1H), 8.68 (d, J=6.8 Hz, 1H), 8.18 (d, J=4.3Hz, 3H), 8.01 (d, J=8.5 Hz, 1H), 7.76 (dd, J=7.8, 4.3 Hz, 1H), 7.62 (d,J=8.3 Hz, 1H), 7.42 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.8 Hz, 2H), 4.84-4.69(m, 1H), 4.47-4.36 (m, 1H), 4.14-4.10 (m, 1H), 4.07-3.96 (m, J=12.8 Hz,1H), 3.33-3.25 (m, 1H), 2.71 (s, 3H), 2.11-1.93 (m, 4H), 1.77-1.53 (m,2H), 1.34 (dd, J=6.9, 2.4 Hz, 3H).

Example 613.4-[4-(5-Methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carbohydroxamicacid

Step 1

To a solution of triphosgene (0.064 g, 0.22 mmol) in anhydrous1,2-dichloroethane (2.0 mL) in a large scintillation vial at 0° C. underN₂ was added a solution of5-methyl-6-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl (0.075g, 0.20 mmol) and DIPEA (0.14 mL, 0.10 g, 0.79 mmol) in anhydrous1,2-dichloroethane (1.0 mL+2×0.5 mL rinses) dropwise. The yellowishsolution stirred at 0° C. for about 60 min. Additional DIPEA (0.14 mL,0.10 g, 0.79 mmol) was added, followed immediately by hydroxylamine HCl(0.041 g, 0.59 mmol). The resulting solution was heated to 75° C. Afterseveral hours, LC-MS showed primarily starting material, and no obvioussign of the desired product. Additional DIPEA (0.210 mL, 0.15 g, 1.19mmol) and hydroxylamine HCl (0.041 g, 0.59 mmol) were added, and thereaction was heated to 70° C. overnight. The mixture was partitionedbetween DCM and saturated aqueous NaHCO₃ solution and separated. Theaqueous layer was re-extracted with DCM. The organic layers werecombined and washed with water, then brine, then dried over Na₂SO₄,filtered, and concentrated. The residue was purified by preparative HPLCon the Gilson (5 to 40% MeCN-95 to 60% water (both with 0.1% TFA) over15 min.; Phenomenex Gemini 5 m NX-C₁₈ 100 Å 150×30 mm column). Thefractions were combined and partitioned between saturated aqueous NaHCO₃solution and DCM, then separated, dried with Na₂SO₄, and concentrated toyield the desired compound as the free base, a white solid (0.017 g,24%). Analysis: LCMS m/z=367 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.08(d, J=2.0 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.89 (s, 1H), 7.68 (d, J=1.3Hz, 1H), 7.53 (d, J=9.3 Hz, 1H), 7.37-7.30 (m, 2H), 7.20 (d, J=9.3 Hz,1H), 7.12-7.05 (m, 2H), 4.62 (tt, J=8.1, 3.8 Hz, 1H), 3.71-3.61 (m, 2H),3.13 (ddd, J=13.2, 9.5, 3.1 Hz, 2H), 2.54 (s, 3H), 1.99-1.89 (m, 2H),1.59-1.47 (m, 2H).

Example 614.2-(Dimethylamino)-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]ethanone

To a suspension of 2-(dimethylamino)acetic acid (0.027 g, 0.26 mmol) andHATU (0.10 g, 0.26 mmol) in anhydrous DCM (2.00 mL) in a scintillationvial at RT under N₂ was added DIPEA (0.15 mL, 0.11 g, 0.88 mmol). Themixture stirred for ˜20 min. before adding8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline (0.070 g, 0.22 mmol) andstirring at RT overnight. The mixture was partitioned between EtOAc andsaturated aqueous NH₄Cl solution and separated. The organic layer waswashed with water, saturated aqueous NaHCO₃ solution, and brine, thendried over Na₂SO₄, filtered, and concentrated. Silica gel chromatographyon the ISCO (0 to 100% (40% 20:1:1 EtOH:NH₄OH:H₂O-60% EtOAc)-100 to 0%hexanes; 24 g column) yielded the desired compound as an off-white solid(0.088 g, 99%). Analysis: LCMS m/z=404 (M+1); ¹H NMR (400 MHz, DMSO-d₆)δ: 8.97 (dd, J=4.3, 1.8 Hz, 1H), 8.37 (dd, J=8.2, 1.9 Hz, 1H), 7.86 (d,J=8.5 Hz, 1H), 7.59-7.52 (m, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.42-7.35 (m,2H), 7.15-7.08 (m, 2H), 4.77-4.68 (m, 1H), 3.97-3.86 (m, 1H), 3.80-3.69(m, J=13.8 Hz, 1H), 3.60 (br. s., 2H), 2.68 (s, 3H), 2.45 (s, 6H),2.10-1.93 (m, 2H), 1.75-1.64 (m, 1H), 1.64-1.53 (m, 1H).

Example 615.4-[4-(5-Methylimidazo[1,2-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

To a solution of 1,1′-carbonyldiimidazole (0.048 g, 0.30 mmol) inanhydrous DMF (2.0 mL) in a scintillation vial at RT under N₂ was addedNH₄Cl (0.018 g, 0.35 mmol) followed by DIPEA (0.17 mL, 0.13 g, 0.99mmol). The solution was stirred at RT for about two hours, and the solidNH₄Cl gradually dissolved.5-Methyl-6-[4-(4-piperidyloxy)-phenyl]imidazo[1,2-a]pyridine 2HCl (0.075g, 0.20 mmol) was then added, and the reaction was stirred at RTovernight. The mixture was partitioned between EtOAc and saturatedaqueous NH₄Cl solution and separated. The organic layer was washed withwater, saturated NaHCO₃ solution, and brine, then dried over Na₂SO₄,filtered, and concentrated. Silica gel chromatography on the ISCO (0 to100% (40% 20:1:1 EtOH: NH₄OH:H₂O-60% EtOAc)-100 to 0% hexanes; 24 gcolumn) yielded the desired compound as a white solid (0.049 g, 71%).Analysis: LCMS m/z=351 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.89 (s, 1H),7.68 (d, J=1.3 Hz, 1H), 7.53 (d, J=9.3 Hz, 1H), 7.37-7.30 (m, 2H), 7.21(d, J=9.3 Hz, 1H), 7.12-7.05 (m, 2H), 5.97 (s, 2H), 4.61 (tt, J=8.2, 3.9Hz, 1H), 3.75-3.65 (m, 2H), 3.12 (ddd, J=13.2, 9.5, 3.1 Hz, 2H), 2.54(s, 3H), 1.99-1.88 (m, 2H), 1.59-1.46 (m, 2H).

Example 616.[(2R)-1-Methylpyrrolidin-2-yl]-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone

To a suspension of (2R)-1-methylpyrrolidine-2-carboxylic acid HCl (0.037g, 0.23 mmol) and HATU (0.079 g, 0.21 mmol) in anhydrous DCM (2.00 mL)in a scintillation vial at RT under N₂ was added DIPEA (0.13 mL, 0.097g, 0.75 mmol). The mixture stirred for ˜20 min. before adding8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline (0.060 g, 0.19 mmol) andstirring at RT for ˜72 hours. The mixture was partitioned between EtOAcand saturated aqueous NH₄Cl solution and separated. The organic layerwas washed with water, saturated aqueous NaHCO₃ solution, and brine,then dried over Na₂SO₄, filtered, and concentrated. Silica gelchromatography on the ISCO (0 to 100% (50% 20:1:1 EtOH:NH₄OH:H₂O-50%EtOAc)-100 to 0% hexanes; 24 g column) yielded the desired compound asan off-white solid (0.077 g, 95%). Analysis: LCMS m/z=430 (M+1); ¹H NMR(400 MHz, DMSO-d₆) δ: 8.97 (dd, J=4.3, 1.8 Hz, 1H), 8.37 (dd, J=8.3, 1.8Hz, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.59-7.52 (m, 1H), 7.48 (d, J=8.5 Hz,1H), 7.38 (d, J=8.8 Hz, 2H), 7.16-7.08 (m, 2H), 4.78-4.67 (m, J=3.5 Hz,1H), 4.05-3.75 (m, 2H), 3.66 (br. s., 1H), 3.54-3.43 (m, J=9.5 Hz, 1H),3.25-3.16 (m, 1H), 2.68 (s, 3H), 2.44 (s, 3H), 2.26 (br. s., 1H),2.11-1.93 (m, 2H), 1.92-1.68 (m, 4H), 1.68-1.51 (m, 2H).

Example 617.[(2S)-1-Methylpyrrolidin-2-yl]-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone

To a suspension of (2S)-1-methylpyrrolidine-2-carboxylic acid hydrate(0.033 g, 0.23 mmol) and HATU (0.079 g, 0.21 mmol) in anhydrous DCM(2.00 mL) in a scintillation vial at RT under N₂ was added DIPEA (0.13mL, 0.097 g, 0.75 mmol). The mixture stirred for ˜20 min. before adding8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline (0.060 g, 0.19 mmol) andstirring at RT for ˜72 hours. The mixture was partitioned between EtOAcand saturated aqueous NH₄Cl solution and separated. The organic layerwas washed with water, saturated aqueous NaHCO₃ solution, and brine,then dried over Na₂SO₄, filtered, and concentrated. Silica gelchromatography on the ISCO (0 to 100% (50% 20:1:1 EtOH:NH₄OH:H₂O-50%EtOAc)-100 to 0% hexanes; 24 g column) yielded the desired compound asan off-white solid (0.077 g, 95%). Analysis: LCMS m/z=430 (M+1); ¹H NMR(400 MHz, DMSO-d₆) δ 8.97: (dd, J=4.0, 1.8 Hz, 1H), 8.37 (dd, J=8.3, 1.8Hz, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.58-7.52 (m, 1H), 7.48 (d, J=8.3 Hz,1H), 7.42-7.35 (m, J=8.5 Hz, 2H), 7.16-7.08 (m, 2H), 4.78-4.67 (m, 1H),4.72 (dt, J=7.0, 3.5 Hz, 1H), 4.07-3.58 (m, 4H), 3.52-3.40 (m, 2H),3.28-3.16 (m, 2H), 2.68 (s, 3H), 2.60-2.52 (m, 1H), 2.45 (s, 3H), 2.27(br. s., 1H), 1.99 (s, 2H), 1.93-1.67 (m, 4H), 1.67-1.52 (m, 2H).

Example 618. S-Isopropyl4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbothioate

To a solution of 8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline (0.060g, 0.19 mmol) in anhydrous DCM (2.0 mL) in a large scintillation vial at0° C. under N₂ was added a solution of DIPEA (0.066 mL, 0.049 g, 0.38mmol) followed by S-isopropyl chloromethanethioate (0.035 mL, 0.039 g,0.28 mmol) dropwise. The mixture was stirred at 0° C. for ˜90 min. Thereaction was quenched by adding ˜2 mL of saturated aqueous NaHCO₃solution, then partitioned between EtOAc and saturated aqueous NH₄Clsolution and separated. The organic layer was washed with water,saturated aqueous NaHCO₃ solution, and brine, then dried over Na₂SO₄,filtered, and concentrated. Silica gel chromatography on the ISCO (0 to100% EtOAc-100 to 0% hexanes; 24 g column) yielded the desired productas an off-white waxy solid (0.0706 g, 89%). Analysis: LCMS m/z=421(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.97 (dd, J=4.0, 1.8 Hz, 1H), 8.37(dd, J=8.2, 1.9 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.55 (dd, J=8.2, 4.1Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.41-7.34 (m, 2H), 7.15-7.07 (m, 2H),4.75-4.67 (m, 1H), 3.77 (br. s., 2H), 3.55-3.43 (m, 1H), 3.42-3.36 (m,2H), 2.68 (s, 3H), 2.05-1.94 (m, 2H), 1.63 (dtd, J=12.7, 8.5, 4.0 Hz,2H), 1.29 (d, J=6.8 Hz, 6H).

Example 619.2-Amino-2-methyl-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]propan-1-one

Step 1

To a suspension of 2-(tert-butoxycarbonylamino)-2-methyl-propanoic acid(0.054 g, 0.26 mmol) and HATU (0.10 g, 0.26 mmol) in anhydrous DCM (2.00mL) in a large scintillation vial at RT under N₂ was added DIPEA (0.15mL, 0.11 g, 0.88 mmol). The mixture stirred for ˜20 min. before adding8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline (0.070 g, 0.22 mmol) andstirring at RT overnight. The mixture was partitioned between EtOAc andsaturated aqueous NH₄Cl solution and separated. The organic layer waswashed with water, saturated aqueous NaHCO₃ solution, and brine, thendried over Na₂SO₄, filtered, and concentrated. Silica gel chromatographyon the ISCO (0 to 100% EtOAc-hexanes; 24 g column) yielded tert-butylN-[1,1-dimethyl-2-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-2-oxo-ethyl]carbamateas a white foam.

Step 2

To a solution of tert-butylN-[1,1-dimethyl-2-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-2-oxo-ethyl]carbamatein anhydrous EtOAc (10 mL) in a small RBF at RT under N₂ was added HCl(4 mol/L) in 1,4-dioxane (5 mL, 20 mmol) dropwise. A yellow precipitateimmediately began to form. The mixture stirred overnight. The reactionwas concentrated to yield a tan solid. Analysis showed that somehydrolysis of the amide had occurred. The residue was purified bypreparative HPLC on the Gilson (5 to 40% MeCN-95 to 60% water (both with0.1% TFA) over 15 min.; Phenomenex Gemini 5 μm NX-C₁₈ 100 Å 150×30 mmcolumn). The good fractions were combined and partitioned betweensaturated aqueous NaHCO₃ solution and DCM, then separated, dried withNa₂SO₄, and concentrated to yield the desired compound as the free base,a white solid (0.0488 g, 55%). Analysis: LCMS m/z=404 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ: 8.97 (dd, J=4.1, 1.9 Hz, 1H), 8.37 (dd, J=8.3, 1.8 Hz,1H), 7.85 (d, J=8.3 Hz, 1H), 7.59-7.52 (m, 1H), 7.48 (d, J=8.5 Hz, 1H),7.41-7.34 (m, 2H), 7.15-7.06 (m, 2H), 4.69 (tt, J=7.9, 3.9 Hz, 1H), 4.29(br. s., 2H), 3.75-3.41 (m, 2H), 2.68 (s, 3H), 2.05-1.88 (m, 3H),1.67-1.54 (m, 2H), 1.28 (s, 6H).

Example 620.[4-[4-(8-Methyl-7-quinolyl)phenoxy]-1-piperidyl]-[(2R)-pyrrolidin-2-yl]methanone

Step 1

To a suspension of (2R)-1-tert-butoxycarbonylpyrrolidine-2-carboxylicacid (0.049 g, 0.23 mmol) and HATU (0.079 g, 0.21 mmol) in anhydrous DCM(2.00 mL) in a scintillation vial at RT under N₂ was added DIPEA (0.13mL, 0.097 g, 0.75 mmol). The mixture stirred for ˜20 min. before adding8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline (0.060 g, 0.19 mmol) andstirring at RT for ˜72 hours. The reaction was partitioned between EtOAcand saturated aqueous NH₄Cl solution and separated. The organic layerwas washed with water, saturated aqueous NaHCO₃ solution, and brine,then dried over Na₂SO₄, filtered, and concentrated. Silica gelchromatography on the ISCO (0 to 100% (10% 20:1:1 EtOH:NH₄OH:H₂O-90%EtOAc)-100 to 0% hexanes; 24 g column) yielded tert-butyl(2R)-2-[4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl]pyrrolidine-1-carboxylateas a white foam.

Step 2

To a solution of tert-butyl(2R)-2-[4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl]pyrrolidine-1-carboxylatein anhydrous DCM (3 mL) in a small RBF at RT under N₂ was addedtrifluoroacetic acid (1 mL, 1.508 g, 13.23 mmol). The mixture stirred atRT for ˜2 hours before the reaction was concentrated. In order togenerate the free base, the residue was dissolved in methanol and loadedonto a Phenomenex Strata-X-C 33u Polymeric Strong Cation 2 g/20 mL GigaTube, then eluted using 2.0 M ammonia in methanol. The eluent wasconcentrated to yield the desired compound as an off-white solid (0.0691g, 88%). Analysis: LCMS m/z=416 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.97(dd, J=4.0, 1.8 Hz, 1H), 8.37 (dd, J=8.3, 1.8 Hz, 1H), 7.86 (d, J=8.3Hz, 1H), 7.55 (dd, J=8.2, 4.1 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.42-7.34(m, 2H), 7.16-7.08 (m, 2H), 4.72 (qt, J=7.7, 3.8 Hz, 1H), 3.99-3.85 (m,2H), 3.85-3.71 (m, 1H), 3.02 (dt, J=10.6, 5.4 Hz, 1H), 2.72-2.63 (m,4H), 2.11-1.92 (m, 3H), 1.76-1.51 (m, 5H).

Example 621.[4-[4-(8-Methyl-7-quinolyl)phenoxy]-1-piperidyl]-[(2S)-pyrrolidin-2-yl]methanone

Step 1

To a suspension of (2S)-1-tert-butoxycarbonylpyrrolidine-2-carboxylicacid (0.049 g, 0.23 mmol) and HATU (0.079 g, 0.21 mmol) in anhydrous DCM(2.00 mL) in a scintillation vial at RT under N₂ was added DIPEA (0.13mL, 0.097 g, 0.75 mmol). The mixture stirred for ˜20 min. before adding8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline (0.060 g, 0.19 mmol) andstirring at RT for ˜72 hours. The reaction was partitioned between EtOAcand saturated aqueous NH₄Cl solution and separated. The organic layerwas washed with water, saturated aqueous NaHCO₃ solution, and brine,then dried over Na₂SO₄, filtered, and concentrated. Silica gelchromatography on the ISCO (0 to 100% (10% 20:1:1 EtOH:NH₄OH:H₂O-90%EtOAc)-100 to 0% hexanes; 24 g column) yielded tert-butyl(2S)-2-[4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl]pyrrolidine-1-carboxylateas a white foam.

Step 2

To a solution of tert-butyl(2S)-2-[4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl]pyrrolidine-1-carboxylatein anhydrous DCM (3 mL) in a small RBF at RT under N₂ was addedtrifluoroacetic acid (1 mL, 1.508 g, 13.23 mmol). The mixture stirred atRT for ˜2 hours before the reaction was concentrated. In order togenerate the free base, the residue was dissolved in methanol and loadedonto a Phenomenex Strata-X-C 33u Polymeric Strong Cation 2 g/20 mL GigaTube, then eluted using 2.0 M ammonia in methanol. The eluent wasconcentrated to yield the desired compound as an off-white solid (0.0641g, 82%). Analysis: LCMS m/z=416 (M+1); 1H NMR (400 MHz, DMSO-d6) δ: 8.97(dd, J=4.1, 1.9 Hz, 1H), 8.37 (dd, J=8.3, 1.8 Hz, 1H), 7.86 (d, J=8.5Hz, 1H), 7.55 (dd, J=8.3, 4.0 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.41-7.35(m, 2H), 7.16-7.08 (m, J=8.5 Hz, 2H), 4.78-4.65 (m, J=7.7, 7.7, 3.6, 3.6Hz, 1H), 4.00-3.85 (m, 2H), 3.85-3.71 (m, J=15.4, 15.4 Hz, 1H), 3.01(dt, J=10.6, 5.4 Hz, 1H), 2.71-2.61 (m, 4H), 2.10-1.93 (m, 3H),1.76-1.51 (m, 5H).

Example 622.[1-(Methylamino)cyclopropyl]-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone

Step 1

1-[tert-butoxycarbonyl(methyl)amino]cyclopropanecarboxylic acid. To asolution of 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid(0.250 g, 1.24 mmol) in anhydrous THF (6.2 mL) in a small RBF at 0° C.under N₂ was added iodomethane (0.155 mL, 0.353 g, 2.48 mmol) followedby NaH (0.149 g, 3.73 mmol). Gas was vigorously evolved. After ˜15 min.,the ice bath was removed, and the mixture was stirred at RT overnight.The white suspension was cooled to 0° C. and quenched by carefullyadding water dropwise until gas was no longer evolved. The reaction wasconcentrated to remove the THF, and the residue was dissolved in ˜10 mLof water. This aqueous layer was extracted with 15 mL of ether; theether layer was then extracted with 10 mL of saturated aqueous NaHCO₃solution. The two aqueous layers were combined in a flask with 10 mL ofEtOAc, cooled to 0° C., and acidified to pH ˜2 by dropwise addition of10% aqueous KHSO₄ solution. The mixture was transferred to a separatoryfunnel with 10 mL of additional EtOAc, the layers were separated, andthe aqueous layer was re-extracted with 2×20 mL of EtOAc. The organiclayers were combined and washed with 5 mL of water, then brine, thendried over Na₂SO₄, filtered, concentrated, and dried under vacuum toyield the desired compound as a white, waxy solid (0.264 g, 99%). ¹H NMR(400 MHz, DMSO-d₆) δ 12.46 (br. s., 1H), 2.84-2.71 (m, 3H), 1.42-1.32(m, 10H), 1.18-1.08 (m, 2H).

Step 2

To a suspension of1-[tert-butoxycarbonyl(methyl)amino]cyclopropanecarboxylic acid (0.053g, 0.24 mmol) and HATU (0.079 g, 0.21 mmol) in anhydrous DCM (2.00 mL)in a large scintillation vial at RT under N₂ was added DIPEA (0.13 mL,0.097 g, 0.75 mmol). The mixture stirred for ˜20 min. before adding8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline (0.060 g, 0.19 mmol) andstirring at RT overnight. The mixture was partitioned between EtOAc andsat. aqueous NH₄Cl solution and separated. The organic layer was washedwith water, sat. NaHCO₃ solution, and brine, then dried over Na₂SO₄,filtered, and concentrated. Silica gel chromatography on the ISCO (0 to100% EtOAc-100 to 0% hexanes; 24 g column) yielded tert-butylN-methyl-N-[1-[4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl]cyclopropyl]carbamateas a white foam.

Step 3

To a solution of tert-butylN-methyl-N-[1-[4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl]cyclopropyl]carbamatein anhydrous DCM (3.0 mL) in a small RBF at RT under N₂ was addedtrifluoroacetic acid (0.5 mL, 0.8 g, 7 mmol). After ˜2 hrs., thereaction was concentrated. In order to generate the free base, theresidue was dissolved in methanol and loaded onto a PhenomenexStrata-X-C 33u Polymeric Strong Cation 2 g/20 mL Giga Tube, then elutedusing 2.0 M ammonia in methanol. The eluent was concentrated to yieldthe desired compound as a white solid (0.0511 g, 65%). Analysis: LCMSm/z=416 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.97 (dd, J=4.3, 1.8 Hz,1H), 8.37 (dd, J=8.3, 1.8 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.55 (dd,J=8.2, 4.1 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.41-7.34 (m, 2H), 7.12 (s,1H), 7.15-7.09 (m, 2H), 4.71 (tt, J=7.9, 3.7 Hz, 1H), 4.02 (br. s., 2H),2.68 (s, 3H), 2.23 (s, 3H), 2.06-1.96 (m, J=11.3 Hz, 2H), 1.70-1.53 (m,J=8.5 Hz, 2H), 0.87-0.80 (m, 2H), 0.70-0.63 (m, 2H).

Example 623.3-Amino-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]propan-1-one,2HCl

Step 1

To a suspension of 3-(tert-butoxycarbonylamino)propanoic acid (0.043 g,0.23 mmol) and HATU (0.079 g, 0.21 mmol) in anhydrous DCM (2.00 mL) in ascintillation vial at RT under N₂ was added DIPEA (0.13 mL, 0.097 g,0.75 mmol). The mixture stirred for ˜20 min. before adding8-methyl-7-[4-(4-piperidyloxy)phenyl]quinolone (0.060 g, 0.19 mmol) andstirring at RT overnight. The mixture was partitioned between EtOAc andsaturated aqueous NH₄Cl solution and separated. The organic layer waswashed with water, saturated aqueous NaHCO₃ solution, and brine, thendried over Na₂SO₄, filtered, and concentrated. Silica gel chromatographyon the ISCO (0 to 100% EtOAc-100 to 0% hexanes; 24 g column) yieldedtert-butylN-[3-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-3-oxo-propyl]carbamateas a white foam/clear, colorless oil.

Step 2

To a solution of tert-butylN-[3-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-3-oxo-propyl]carbamate(0.080 g, 0.16 mmol) in anhydrous DCM (5 mL) in a small RBF at RT underN₂ was added 4.0 M HCl in 1,4-Dioxane (5 mL, 20 mmol) dropwise. Themixture became cloudy after several minutes, and then became clearer asa small amount of precipitate stuck to the walls of the flask. Thereaction stirred at RT for about two hours before the mixture wasconcentrated. In order to generate the free base, the residue wasdissolved in methanol and loaded onto a Phenomenex Strata-X-C 33uPolymeric Strong Cation 2 g/20 mL Giga Tube, then eluted using 2.0 Mammonia in methanol. The eluent was concentrated. When several attemptsto concentrate the compound from dichloromethane/ether failed to yieldan easily weighable solid, the HCl salt was synthesized by dissolvingthe compound in anhydrous dichloromethane and treating with a slightexcess of 2.0 M HCl-ether. Concentration and drying under vacuum yieldedthe desired compound as the dihydrochloride salt, a yellow solid (0.0652g, 75%). Analysis: LCMS m/z=390 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.00(dd, J=4.3, 1.8 Hz, 1H), 8.46 (d, J=7.8 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H),7.80 (br. s., 3H), 7.61 (dd, J=8.2, 4.1 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H),7.42-7.36 (m, 2H), 7.16-7.09 (m, 2H), 4.73 (tt, J=7.8, 3.7 Hz, 1H),3.98-3.89 (m, 1H), 3.71 (dt, J=13.7, 5.1 Hz, 1H), 3.01 (sxt, J=5.9 Hz,2H), 2.74 (t, J=6.3 Hz, 2H), 2.69 (s, 3H), 2.11-1.93 (m, 2H), 1.75-1.54(m, 2H).

Example 624

2-Isopropoxy-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]ethanone,HCl

To a suspension of 2-isopropoxyacetic acid (0.027 g, 0.23 mmol) and HATU(0.079 g, 0.21 mmol) in anhydrous DCM (2.00 mL) in a scintillation vialat RT under N₂ was added DIPEA (0.13 mL, 0.097 g, 0.75 mmol). Themixture stirred for ˜20 min. before adding8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline (0.060 g, 0.19 mmol) andstirring at RT overnight. The mixture was partitioned between EtOAc andsaturated aqueous NH₄Cl solution and separated. The organic layer waswashed with water, saturated aqueous NaHCO₃ solution, and brine, thendried over Na₂SO₄, filtered, and concentrated. Silica gel chromatographyon the ISCO (0 to 100% EtOAc-100 to 0% hexanes; 24 g column) yielded aclear, colorless oil. The HCl salt was synthesized by dissolving thecompound in anhydrous dichloromethane and treating with a slight excessof 2.0 M HCl-ether, then concentrating and drying under vacuum to yieldthe desired compound as a yellow solid (0.0627 g, 73%). Analysis: LCMSm/z=419 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.08 (dd, J=4.5, 1.5 Hz,1H), 8.69 (d, J=7.8 Hz, 1H), 8.01 (d, J=8.3 Hz, 1H), 7.76 (dd, J=8.0,4.5 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.44-7.36 (m, 2H), 7.18-7.10 (m,2H), 4.72 (tt, J=7.8, 3.6 Hz, 1H), 4.11 (d, J=1.3 Hz, 2H), 3.93-3.84 (m,2H), 3.78-3.69 (m, J=12.5 Hz, 3H), 3.40-3.32 (m, 2H), 3.32-3.23 (m, 2H),2.71 (s, 3H), 2.09-1.92 (m, J=19.3 Hz, 2H), 1.74-1.62 (m, 1H), 1.62-1.50(m, 1H), 1.12 (d, J=6.0 Hz, 6H).

Example 625.[2-[4-[4-(8-Methyl-7-quinolyl)phenoxy]-1-piperidyl]-2-oxo-ethyl]acetate

To a solution of 8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline (0.060g, 0.19 mmol) and DIPEA (0.13 mL, 0.097 g, 0.75 mmol) in anhydrous DCM(2.00 mL) in a scintillation vial at RT under N₂ was added(2-chloro-2-oxo-ethyl) acetate (0.026 mL, 0.033 g, 0.24 mmol) dropwise.The mixture was stirred at RT overnight. The mixture was partitionedbetween EtOAc and saturated aqueous NH₄Cl solution and separated. Theorganic layer was washed with water, saturated aqueous NaHCO₃ solution,and brine, then dried over Na₂SO₄, filtered, and concentrated. Silicagel chromatography on the ISCO (0 to 100% EtOAc-100 to 0% hexanes; 24 gcolumn) yielded the desired compound as an off-white solid (0.065 g,82%). Analysis: LCMS m/z=419 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.97(dd, J=4.1, 1.9 Hz, 1H), 8.37 (dd, J=8.3, 1.8 Hz, 1H), 7.86 (d, J=8.5Hz, 1H), 7.55 (dd, J=8.2, 4.1 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.41-7.35(m, 2H), 7.15-7.09 (m, J=8.8 Hz, 2H), 4.81 (s, 2H), 4.72 (tt, J=7.7, 3.7Hz, 1H), 3.91-3.79 (m, 1H), 3.70-3.58 (m, J=14.1 Hz, 1H), 3.31-3.25 (m,1H), 2.68 (s, 3H), 2.09 (s, 3H), 2.07-1.91 (m, 2H), 1.75-1.63 (m, 1H),1.63-1.51 (m, 1H).

Example 626.2-Hydroxy-1-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]ethanone

To a suspension of[2-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-2-oxo-ethyl] acetate(0.060 g, 0.14 mmol) in methanol (2 mL) in a scintillation vial at RTunder N₂ was added 1.0 N aqueous lithium hydroxide solution (0.22 mL,0.22 mmol). The mixture became homogeneous, and was stirred at RT for˜2.5 hrs. before adding 1.0 N aqueous HCl solution (0.220 mL, 0.22mmol), then partially concentrating to remove the methanol. The residuewas partitioned between ethyl acetate and saturated aqueous NH₄Clsolution and separated. The organic layer was washed with water,saturated NaHCO₃ solution, and brine, then dried over Na₂SO₄, filtered,and concentrated to yield the desired compound as an off-white solid(0.0509 g, 94%). Analysis: LCMS m/z=377 (M+1); ¹H NMR (400 MHz, DMSO-d₆)δ: 8.97 (dd, J=4.3, 1.8 Hz, 1H), 8.37 (dd, J=8.3, 1.8 Hz, 1H), 7.85 (d,J=8.3 Hz, 1H), 7.59-7.52 (m, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.42-7.34 (m,2H), 7.15-7.08 (m, 2H), 4.71 (tt, J=7.8, 3.7 Hz, 1H), 4.54 (t, J=5.5 Hz,1H), 4.12 (d, J=5.5 Hz, 2H), 3.97-3.84 (m, 1H), 3.67-3.55 (m, J=14.3 Hz,1H), 3.32-3.24 (m, 2H), 2.68 (s, 3H), 2.07-1.93 (m, 2H), 1.73-1.52 (m,2H).

Example 627.(1-Aminocyclobutyl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone

Step 1

To a suspension of 1-(tert-butoxycarbonylamino)cyclobutanecarboxylicacid (0.053 g, 0.24 mmol) and HATU (0.079 g, 0.21 mmol) in anhydrous DCM(2.00 mL) in a scintillation vial at RT under N₂ was added DIPEA (0.13mL, 0.097 g, 0.75 mmol). The mixture stirred for ˜20 min. before adding8-methyl-7-[4-(4-piperidyloxy)phenyl]quinoline (0.060 g, 0.19 mmol) andstirring at RT overnight. The mixture was partitioned between EtOAc andsaturated aqueous NH₄Cl solution and separated. The organic layer waswashed with water, saturated aqueous NaHCO₃ solution, and brine, thendried over Na₂SO₄, filtered, and concentrated. Silica gel chromatographyon the ISCO (0 to 100% EtOAc-100 to 0% hexanes; 24 g column) yieldedtert-butylN-[1-[4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl]cyclobutyl]carbamateas a white foam.

Step 2

To a solution of tert-butylN-[1-[4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbonyl]cyclobutyl]carbamatein anhydrous DCM (5.0 mL) in a small RBF at RT under N₂ was added 4.0 MHCl in 1,4-dioxane (5.0 mL, 20 mmol) dropwise. The reaction was stirredat RT for about two hours before it was concentrated to yield a yellowsolid. The residue was purified by preparative HPLC on the Gilson (5 to40% MeCN-95 to 60% water (both with 0.1% TFA) over 15 min.; PhenomenexGemini 5 m NX-C₁₈ 100 Å 150×30 mm column). The good fractions werecombined and partitioned between saturated aqueous NaHCO₃ solution andDCM, then separated, dried with Na₂SO₄, and concentrated to yield thedesired compound as the free base, a clear, colorless oil whicheventually crystallized into a white solid. (0.0409 g, 52%). Analysis:LCMS m/z=416 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (dd, J=4.1, 1.9 Hz,1H), 8.36 (dd, J=8.2, 1.9 Hz, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.55 (dd,J=8.2, 4.1 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.41-7.34 (m, 2H), 7.15-7.07(m, 2H), 4.74-4.64 (m, J=7.9, 4.1, 4.1 Hz, 1H), 3.88 (br. s., 2H), 3.26(br. s., 1H), 2.68 (s, 3H), 2.59-2.52 (m, 2H), 2.21 (br. s., 2H), 1.97(br. s., 2H), 1.93-1.79 (m, 3H), 1.74-1.44 (m, 3H).

Example 628

N-Ethyl-4-(4-imidazo[1,2-a]pyridin-7-ylphenoxy)piperidine-1-carboxamide,HCl

Step 1

tert-Butyl4-(4-imidazo[1,2-a]pyridin-7-ylphenoxy)piperidine-1-carboxylate HClPalladium acetate (0.021 g, 0.094 mmol) and triphenylphosphine (0.10 g,0.38 mmol) were combined in a flask in 1,4-dioxane (6.0 mL). Afterstirring for 30 min, DMF (5.7 g, 6.0 mL, 78 mmol), tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]piperidine-1-carboxylate(0.75 g, 1.9 mmol), 7-bromoimidazo[1,2-a]pyridine (0.44 g, 2.2 mmol) andaq. Na₂CO₃ (0.5 M) (12.0 mL, 6.0 mmol) were added and the flask washeated under nitrogen at 90° C. overnight. The mixture was diluted withwater (60 mL) then extracted with EtOAc (3×50 mL). The organic extractswere combined, washed with brine (50 mL), dried over sodium sulfatefiltered and concentrated in vacuo. The residue was dissolved in EtOAc(40 mL) then treated with 2M HCl in ether (1.5 mL) with stirring. Theresultant solids were collected by filtration, washed with EtOAc (30 mL)and hexane (10 mL), then dried on a Buchner funnel to afford tert-butyl4-(4-imidazo[1,2-a]pyridin-7-ylphenoxy)piperidine-1-carboxylate HCl(0.495 g, 62% Yield) as a beige solid. LCMS (ESI): 394 (M+1); ¹H NMR(400 MHz, DMSO-d₆) δ 8.91 (d, J=7.2 Hz, 1H), 8.30 (d, J=1.5 Hz, 1H),8.14 (d, J=2.0 Hz, 1H), 8.09 (s, 1H), 7.93-7.84 (m, 3H), 7.19 (d, J=8.8Hz, 2H), 4.71 (dt, J=7.8, 4.1 Hz, 1H), 3.73-3.51 (m, 2H), 3.29-3.14 (m,2H), 1.97-1.88 (m, 2H), 1.61-1.51 (m, 2H), 1.41 (s, 9H).

Step 2. 7-[4-(4-Piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl

Acetyl chloride (0.6 g, 0.5 mL, 7 mmol) was added to ethanol (10.0 mL)and the mixture was then added to tert-butyl4-(4-imidazo[1,2-a]pyridin-7-ylphenoxy)piperidine-1-carboxylate HCl(0.495 g, 1.15 mmol). After stirring at room temperature for 1 h, themixture was heated at 60° C. for 3 h. The mixture was cooled to roomtemperature then diluted with ether (10 mL), which resulted in formationof a gum. The mixture was transferred to a tared flask using methanolthen concentrated in vacuo and dried in vacuo to afford7-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl (0.415 g, 1.13mmol, 98.4% Yield) as a yellow solid with trace ethanol remaining. LCMS(ESI): 294 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.13 (br s, 2H),8.97-8.93 (m, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H),8.12-8.09 (m, 1H), 7.95-7.86 (m, 3H), 7.22 (d, J=9.0 Hz, 2H), 4.86-4.75(m, 1H), 3.31-3.18 (m, 2H), 3.15-3.02 (m, 2H), 2.23-2.10 (m, 2H),1.96-1.82 (m, 2H).

Step 3.N-Ethyl-4-(4-imidazo[1,2-a]pyridin-7-ylphenoxy)piperidine-1-carboxamideHCl

A mixture of 7-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl(0.095 g, 0.26 mmol) and DIPEA (0.15 g, 0.20 mL, 1.1 mmol) in THF (5.0mL) with ACN (1.0 mL) was treated at room temperature with ethylisocyanate (0.045 g, 0.050 mL, 0.63 mmol). After stirring overnight themixture was partitioned between saturated aq. NaHCO₃ (10 mL) and DCM (5mL). The layers were separated, the aq. phase further extracted with DCM(2×10 mL) and the combined organics were dried over sodium sulfate,filtered and concentrated in vacuo. The residue was dissolved in DCM,applied to a silica gel loading cartridge (5 g) and purified on silicagel (12 g, 0-7% methanol:DCM). Product fractions were combined, treatedwith 2M HCl in ether (1 mL) then concentrated in vacuo. The residue wasreconcentrated from ethanol then dried in vacuo to affordN-ethyl-4-(4-imidazo[1,2-a]pyridin-7-ylphenoxy)piperidine-1-carboxamideHCl (0.069 g, 0.17 mmol, 66% Yield) as a hard orange foam. LCMS (ESI):365 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ 14.39 (br s, 1H), 8.93 (d, J=7.3Hz, 1H), 8.32 (d, J=1.8 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 8.10 (s, 1H),7.92-7.87 (m, 3H), 7.19 (d, J=8.8 Hz, 2H), 6.63-6.46 (m, 1H), 4.74-4.66(m, 1H), 3.73-3.68 (m, 2H), 3.17-3.08 (m, 2H), 3.05 (q, J=7.2 Hz, 2H),1.98-1.89 (m, 1H), 1.57-1.46 (m, 2H), 1.01 (t, J=7.2 Hz, 3H).

Example 629.N-Ethyl-4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]piperidine-1-carboxamide,HCl

Step 1. 7-Bromo-8-methyl-imidazo[1,2-a]pyridine

A mixture of 4-bromo-3-methyl-pyridin-2-amine (0.45 g, 2.4 mmol) andbromo-acetaldehyde diethyl acetal (0.98 g, 0.75 mL, 5.0 mmol) in ethanol(2.4 mL) was treated with 48% aq. HBr (0.37 g, 0.25 mL, 2.2 mmol) thenthe mixture was heated at 60° C. in a resealable vial. After stirringfor seven days, the mixture was cooled to room temperature, treated with0.5M Na₂CO₃ (10 mL) then extracted with DCM (10 mL then 5 mL). Theorganic extract was dried over Na₂SO₄, filtered and concentrated invacuo. The residue was dissolved in DCM, applied to a silica gel loadingcartridge (5 g) and purified on silica gel (40 g, 0-5% methanol:DCM) toafford 7-bromo-8-methyl-imidazo[1,2-a]pyridine (0.436 g, 2.07 mmol, 86%Yield) after concentration of product containing fractions. LCMS (ESI):211 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.39-8.35 (m, 1H), 7.96 (d,J=1.3 Hz, 1H), 7.55 (d, J=1.3 Hz, 1H), 7.05 (d, J=7.3 Hz, 1H), 2.56 (s,3H).

Step 2. tert-Butyl4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]piperidine-1-carboxylate

Analogous to Example 628 Step 1, 7-bromo-8-methyl-imidazo[1,2-a]pyridineand tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]piperidine-1-carboxylatewere coupled to prepare tert-butyl4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]piperidine-1-carboxylate(0.68 g, 81% yield). LCMS (ESI): 408 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ:8.42 (d, J=7.0 Hz, 1H), 7.93 (d, J=1.3 Hz, 1H), 7.56 (d, J=1.0 Hz, 1H),7.35 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 6.80 (d, J=7.0 Hz, 1H),4.63 (tt, J=8.0, 3.7 Hz, 1H), 3.75-3.63 (m, 2H), 3.26-3.16 (m, 2H), 2.46(s, 3H), 1.98-1.89 (m, 2H), 1.62-1.49 (m, 2H), 1.41 (s, 9H).

Step 3. 8-Methyl-7-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine,2HCl

Analogous to Example 628 Step 2, tert-butyl4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]piperidine-1-carboxylatewas converted to8-methyl-7-[4-(4-piperidyloxy)-phenyl]imidazo[1,2-a]pyridine 2HCl (0.65g, 99% yield). MS (ESI): 308 (M+1); 1H NMR (400 MHz, DMSO-d₆) δ: 14.71(br s, 1H), 9.08 (br s, 2H), 8.81 (d, J=6.8 Hz, 1H), 8.38 (d, J=2.3 Hz,1H), 8.25 (d, J=2.0 Hz, 1H), 7.52-7.40 (m, 3H), 7.19 (d, J=8.8 Hz, 2H),4.81-4.74 (m, 1H), 3.31-3.19 (m, 2H), 3.15-3.04 (m, 2H), 2.56 (s, 3H),2.21-2.10 (m, 2H), 1.95-1.84 (m, 2H).

Step 3. 8-Methyl-7-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine,2HCl

Analogous to Example 628 Step 38-methyl-7-[4-(4-piperidyloxy)phenyl]-imidazo[1,2-a]pyridine 2HCl (0.110g, 0.289 mmol) was converted toN-ethyl-4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]piperidine-1-carboxamideHCl (0.091 g, 0.22 mmol, 76% Yield). LCMS (ESI): 379 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ: 14.52 (br s, 1H), 8.80 (d, J=6.8 Hz, 1H), 8.38 (d,J=2.0 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 7.49-7.41 (m, 3H), 7.16 (d, J=8.5Hz, 2H), 6.56-6.48 (m, 1H), 4.69-4.62 (m, 1H), 3.76-3.67 (m, 2H),3.18-3.01 (m, 4H), 2.55 (s, 3H), 1.99-1.89 (m, 2H), 1.58-1.47 (m, 2H),1.01 (t, J=7.0 Hz, 3H).

Example 630.N-Isopropoxy-4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]piperidine-1-carboxamide,HCl

A mixture of O-isopropylhydroxylamine HCl (0.058 g, 0.52 mmol),N,N′-carbonyldiimidazole (0.071 g, 0.44 mmol) and DIPEA (0.37 g, 0.50mL, 2.9 mmol) in DCM (3.0 mL) was stirred for 2 h, then8-methyl-7-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl (0.076g, 0.20 mmol) was added to the reaction. After stirring overnight, thereaction solution was applied to a silica gel loading column (25 g) thenpurified on silica gel (12 g, 0-5% methanol:DCM). Product containingfractions were concentrated in vacuo then reconcentrated from ethanolicHCl (1 mL, 1M) and ethanol to affordN-isopropoxy-4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]piperidine-1-carboxamideHCl (0.063 g, 0.14 mmol, 71% Yield) as a white foam after drying invacuo. LCMS (ESI)=409 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 14.51 (br s,1H), 9.52 (s, 1H), 8.79 (d, J=7.0 Hz, 1H), 8.36 (d, J=2.3 Hz, 1H), 8.23(d, J=2.0 Hz, 1H), 7.47-7.41 (m, 3H), 7.16 (d, J=8.8 Hz, 2H), 4.70-4.64(m, 1H), 3.87 (quin, J=6.1 Hz, 1H), 3.71-3.60 (m, 2H), 3.14 (ddd,J=13.1, 9.5, 3.3 Hz, 2H), 2.55 (s, 3H), 1.99-1.91 (m, 2H), 1.59-1.50 (m,2H), 1.12 (d, J=6.3 Hz, 6H).

Example 631.4-[4-(8-Methylimidazo[1,2-a]pyridin-7-yl)phenoxy]-N-propyl-piperidine-1-carboxamide,HCl

Analogous to Example 628 Step 3,8-methyl-7-[4-(4-piperidyloxy)phenyl]-imidazo[1,2-a]pyridine 2HCl (0.076g, 0.20 mmol) was reacted with propyl isocyanate to afford4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]-N-propyl-piperidine-1-carboxamideHCl (0.063 g, 0.15 mmol, 73% Yield). LCMS (ESI)=393 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ: 14.73 (br s, 1H), 8.82 (d, J=6.8 Hz, 1H), 8.39 (d,J=2.0 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 7.49-7.41 (m, 3H), 7.16 (d, J=8.8Hz, 2H), 6.56 (br s, 1H), 4.70-4.62 (m, 1H), 3.78-3.67 (m, 2H),3.18-3.06 (m, 2H), 3.03-2.92 (m, 2H), 2.57 (s, 3H), 2.00-1.88 (m, 2H),1.57-1.47 (m, 2H), 1.47-1.36 (m, 2H), 0.83 (t, J=7.4 Hz, 3H).

Example 632.N-Isobutyl-4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]piperidine-1-carboxamide

Analogous to Example 628 Step 3,8-methyl-7-[4-(4-piperidyloxy)phenyl]imidazo[1,2-a]pyridine 2HCl (0.076g, 0.20 mmol) was reacted with isobutyl isocyanate to affordN-isobutyl-4-[4-(8-methylimidazo[1,2-a]pyridin-7-yl)phenoxy]piperidine-1-carboxamide(0.055 g, 0.14 mmol, 68% Yield). LCMS (ESI)=407 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ 8.42 (d, J=7.0 Hz, 1H), 7.93 (d, J=1.3 Hz, 1H), 7.56 (d,J=1.3 Hz, 1H), 7.35 (d, J=7.8 Hz, 2H), 7.08 (d, J=7.9 Hz, 2H), 6.80 (d,J=7.0 Hz, 1H), 6.54 (t, J=5.5 Hz, 1H), 4.65-4.56 (m, 1H), 3.76-3.68 (m,2H), 3.16-3.07 (m, 2H), 2.85 (dd, J=6.9, 5.9 Hz, 2H), 2.46 (s, 3H),1.97-1.89 (m, 2H), 1.75-1.65 (m, 1H), 1.56-1.46 (m, 2H), 0.83 (d, J=6.5Hz, 6H).

Example 633.N-Isobutyl-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

This compound may be synthesized using the procedure for example 537using 1-isocyanato-2-methylpropane.

Example 634.4-[4-(7-Methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

This compound may be synthesized using the procedure for example 539with 7-methyl-6-[4-(4-piperidyloxy)phenyl]pyrazolo[1,5-a]pyridine 2HCl.

Example 635.4-[4-(7-Methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carbohydroxamicacid

This compound may be synthesized using the procedure for example 576starting with7-methyl-6-[4-(4-piperidyloxy)phenyl]pyrazolo[1,5-a]pyridinedihydrochloride.

Example 636.N,N-Dimethyl-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

This compound may be synthesized using the procedure for example 89starting with7-methyl-6-[4-(4-piperidyloxy)phenyl]pyrazolo[1,5-a]pyridine 2HCl anddimethylamine.

Example 637.[4-[4-(7-Methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]-1-piperidyl]-pyrrolidin-1-yl-methanone

This compound may be synthesized using the procedure for example 94starting with7-methyl-6-[4-(4-piperidyloxy)phenyl]pyrazolo[1,5-a]pyridine 2HCl andpyrrolidine.

Example 638.[(3S)-3-Fluoropyrrolidin-1-yl]-[4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]-1-piperidyl]methanone

This compound may be synthesized using the procedure for example 94starting with7-methyl-6-[4-(4-piperidyloxy)phenyl]pyrazolo[1,5-a]pyridine 2HCl andS-3-fluoropyrrolidine.

Example 639.[(3R)-3-Fluoropyrrolidin-1-yl]-[4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]-1-piperidyl]methanone

This compound may be synthesized using the procedure for example 94starting with7-methyl-6-[4-(4-piperidyloxy)phenyl]pyrazolo[1,5-a]pyridine 2HCl andR-3-fluoropyrrolidine.

Example 640. 4-[4-(7-Methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]-N-methylsulfanyl-piperidine-1-carboxamide

This compound may be synthesized using the procedure for example 94starting with7-methyl-6-[4-(4-piperidyloxy)phenyl]pyrazolo[1,5-a]pyridine 2HCl andmethanesulfenamide

Example 641.N-Ethylsulfanyl-4-[4-(7-methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carboxamide

This compound may be synthesized using the procedure for example 94starting with7-methyl-6-[4-(4-piperidyloxy)phenyl]pyrazolo[1,5-a]pyridine 2HCl andethylsulfenamide

Example 642.4-[4-(4-Methyl-3-quinolyl)phenoxy]-N-methylsulfanyl-piperidine-1-carboxamide

This compound may be synthesized using the procedure for example 94starting with 4-methyl-3-[4-(4-piperidyloxy)phenyl]quinolone 2HCl andmethanesulfenamide.

Example 643.4-[4-(4-Methyl-3-quinolyl)phenoxy]-N-ethylsulfanyl-piperidine-1-carboxamide

This compound may be synthesized using the procedure for example 94starting with 4-methyl-3-[4-(4-piperidyloxy)phenyl]quinolone 2HCl andmethanesulfenamide

Example 644.1-[4-[4-(7-Methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]piperidine-1-carbonyl]pyrrolidin-2-one.

This compound may be synthesized using7-methyl-6-[4-(4-piperidyloxy)phenyl]-pyrazolo[1,5-a]pyridine 2HCl andpyrrolidin-2-one

Example 645.1-[4-[4-(4-Methyl-3-quinolyl)phenoxy]piperidine-1-carbonyl]pyrrolidin-2-one

This compound may be synthesized using4-methyl-3-[4-(4-piperidyloxy)phenyl]-quinolone 2HCl andpyrrolidin-2-one

Example 646.4-[4-(7-Methylpyrazolo[1,5-a]pyridin-6-yl)phenoxy]-N-propyl-piperidine-1-carboxamide

This compound may be synthesized using the procedure for example 537using 7-methyl-6-[4-(4-piperidyloxy)phenyl]pyrazolo[1,5-a]pyridine 2HCland 1-isocyanato-3-propane

Example 647.N-ethyl-4-[4-(2-fluoro-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide

This compound may be synthesized using the procedure for example 88 with7-bromo-2-fluoro-8-methyl-quinoline in place of7-bromo-8-methyl-quinoline using the intermediate of example 529 step 2,and reacting with phosphorus oxychloride followed by reaction withtetrabutylammonium fluoride.

A number of embodiments of the invention have been described herein.Nevertheless, As those skilled in the art will appreciate, numerousmodifications and variations of the present invention are possible inlight of the above teachings; without departing from the scope of theinvention that is disclosed herein. It is therefore understood thatwithin the scope of the appended claims, the invention may be practicedotherwise than as specifically described herein, and the scope of theinvention is intended to encompass all such variations.

What is claimed is:
 1. A pharmaceutical composition comprising at leastone compound according to Formula V(a):

or a pharmaceutically acceptable salt thereof, wherein: R^(1b) isselected from —NR⁷R⁸ and —N(OR⁸)R⁷; R⁴ is selected from —H, —(C₁-C₆)alkyl, —OH, —O(C₁-C₆) alkyl, halogen, and —CN; X is selected from —O—and —S—; R⁵ is selected from —H, —C₁-C₇ hydrocarbyl, —C₃-C₆heterocyclyl; halogen, —(C₁-C₃) haloalkyl, —OR^(7a), —CN,—NR^(7a)R^(8a), —O(CH₂)_(n)NR^(7a)R^(8a), —O(CH₂)_(n)OR^(8a),—NR^(8a)(CH₂)_(n)NR^(7a)R^(8a), —NR^(8a)(CH₂)_(n)OR^(8a),—C(═O)NR^(7a)R^(8a), —C(═O)OR^(7a), 5-6 membered heteroaryl andsubstituted 5-6 membered heteroaryl; n is an integer selected from 1, 2,3, and 4; R⁷ is selected from —H, —(C₁-C₇) hydrocarbyl, substituted—(C₁-C₇) hydrocarbyl, —C(═O)R⁸, and —(C₁-C₆) heteroalkyl; R⁸ is selectedfrom —H, and —(C₁-C₆) alkyl, wherein R⁷ can optionally be structurallyconnected to R⁸ to form a 5 to 7 membered heterocyclyl ring; R^(7a) isselected from —H, —(C₁-C₇) hydrocarbyl, substituted —(C₁-C₇)hydrocarbyl, —C(═O)R⁸, and —(C₁-C₆) heteroalkyl; R^(8a) is selected from—H, and —(C₁-C₆) alkyl, wherein R^(7a) can optionally be structurallyconnected to R^(8a) to form a 5 to 7 membered heterocyclyl ring; Q¹, Q²,Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are independently selected from N and C—R¹²,provided that 1, 2 or 3 of Q Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are N, and theremainder of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹²; each R¹² isindependently selected from —H, halogen, —(C₁-C₆) alkyl, —(C₃-C₆)cycloalkyl, 5-6 membered heterocyclyl, —OH, —O(C₁-C₆) alkyl,—O(CH₂)_(p)-(5-6 membered heterocyclyl), —O(CH₂)_(p)—O(C₁-C₆) alkyl,—NH₂, —CN, —NH(C₁-C₆) alkyl, —N(C₁-C₆ alkyl)₂, —NH(CH₂)_(p)—O(C₁-C₆)alkyl, —NH(CH₂)_(p)—N(C₁-C₆ alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl,and —C(═O)N(C₁-C₆ alkyl)₂; and p is an integer selected independentlyfrom 1, 2, 3, and 4; and at least one pharmaceutically acceptableexcipient.
 2. The pharmaceutical composition according to claim 1,wherein X is —O—.
 3. The pharmaceutical composition according to claim1, wherein R⁵ is selected from —H, —(C₁-C₇) hydrocarbyl, and halogen. 4.The pharmaceutical composition according to claim 1, wherein one of Q¹,Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ is N, and the remainder of Q¹, Q², Q³, Q⁴, Q⁵,Q⁶ and Q⁷ are C—R¹².
 5. The pharmaceutical composition according toclaim 4, wherein one of Q² and Q⁶ is N; the other of Q² and Q⁶ is C—R¹²;and Q¹, Q³, Q⁴, Q⁵ and Q⁷ are C—R¹².
 6. The pharmaceutical compositionaccording to claim 1, wherein the compound according to Formula V(a) isselected from:isoxazolidin-2-yl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;[4-(4-isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-isoxazolidin-2-yl-methanone;isoxazolidin-2-yl-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(4-chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-isoxazolidin-2-yl-methanone;{4-[4-(8-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-isoxazolidin-2-yl-methanone;isoxazolidin-2-yl-{4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-{4-[4-(7-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-[4-(4-quinoxalin-2-yl-phenoxy)-piperidin-1-yl]-methanone;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidmethoxyamide;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidmethoxymethylamide;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidethylamide;4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidmethylamide;4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidethylamide;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidhydroxyamide;N-ethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N,N-dimethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-methoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-ethoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-pyrrolidin-1-yl-methanone;N-methyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(1-piperidyl)methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-morpholinomethanone;N-methoxy-4-[4-(8-methoxy-7-quinolyl)phenoxy]piperidine-1-carboxamide;3-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-oxazolidin-2-one;1-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-pyrrolidin-2-one;N-ethyl-4-[4-(2-hydroxy-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-pyrrolidin-1-ylethyl)piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-morpholinoethyl)piperidine-1-carboxamide;(4-isopropylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;(4-methylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(4-morpholino-1-piperidyl)methanone;(4-ethylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;N-(cyclopropylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carb oxamide;N-(2-methoxyethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isobutoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carb oxamide;N-(2-dimethylaminoethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-[2-(1H-imidazol-4-yl)ethyl]-4-[4-(8-methyl-7-quinolyl)phenoxy]¬piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-tetrahydropyran-4-yl-piperidine-1-carboxamide;N-cyclobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbohydroxamic acid;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(oxazinan-2-yl)methanone;N-(cyclobutylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;azepan-1-yl-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide;N-ethyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;N-isobutyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-(cyclopropylmethyl)-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]-N-propoxypiperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carbohydroxamic acid;N-ethoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-ethoxy-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide;N-isobutyl-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carb oxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-methylsulfanyl-piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-ethylsulfanyl-piperidine-1-carboxamide,1-[4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carbonyl]pyrrolidin-2-one;or a pharmaceutically acceptable salt thereof.
 7. The pharmaceuticalcomposition according to claim 6, further comprising an antipsychoticagent.
 8. The pharmaceutical composition according to claim 7, whereinthe antipsychotic agent is clozapine, risperidone, aripiprazole,olanzapine, quetiapine or ziprasidone or a combination thereof.
 9. Thepharmaceutical composition according to claim 1, wherein the compound offormula (Va) is

or a pharmaceutically acceptable salt thereof.
 10. The pharmaceuticalcomposition according to claim 1, wherein the compound of formula (Va)is

or a pharmaceutically acceptable salt thereof.
 11. A method of treatinga subject suffering from a disorder mediated by fatty acid synthase,comprising administering to the subject a therapeutically effectiveamount of a pharmaceutical composition according to claim
 1. 12. Acompound having the formula:

or a pharmaceutically acceptable salt thereof.
 13. A compound having theformula:

or a pharmaceutically acceptable salt thereof.
 14. A method of treatinga subject suffering from a disorder mediated by fatty acid synthase,comprising administering to the subject a therapeutically effectiveamount of a compound according to Formula V(a):

or a pharmaceutically acceptable salt thereof, wherein: R^(1b) isselected from —NR⁷R⁸ and —N(OR⁸)R⁷; R⁴ is selected from —H, —(C₁-C₆)alkyl, —OH, —O(C₁-C₆) alkyl, halogen, and —CN; X is selected from —O—and —S—; R⁵ is selected from —H, —C₁-C₇ hydrocarbyl, —C₃-C₆heterocyclyl; halogen, —(C₁-C₃) haloalkyl, —OR^(7a), —CN,—NR^(7a)R^(8a), —O(CH₂)_(n)NR^(7a)R^(8a), —O(CH₂)_(n)OR^(8a),—NR^(8a)(CH₂)_(n)NR^(7a)R^(8a), —NR^(8a)(CH₂)_(n)OR^(8a),—C(═O)NR^(7a)R^(8a), —C(═O)OR^(7a), 5-6 membered heteroaryl andsubstituted 5-6 membered heteroaryl; n is an integer selected from 1, 2,3, and 4; R⁷ is selected from —H, —(C₁-C₇) hydrocarbyl, substituted—(C₁-C₇) hydrocarbyl, —C(═O)R⁸, and —(C₁-C₆) heteroalkyl; R⁸ is selectedfrom —H, and —(C₁-C₆) alkyl, wherein R⁷ can optionally be structurallyconnected to R⁸ to form a 5 to 7 membered heterocyclyl ring; R^(7a) isselected from —H, —(C₁-C₇) hydrocarbyl, substituted —(C₁-C₇)hydrocarbyl, —C(═O)R⁸, and —(C₁-C₆) heteroalkyl; R^(8a) is selected from—H, and —(C₁-C₆) alkyl, wherein R^(7a) can optionally be structurallyconnected to R^(8a) to form a 5 to 7 membered heterocyclyl ring; Q¹, Q²,Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are independently selected from N and C—R¹²,provided that 1, 2 or 3 of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are N, and theremainder of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹²; each R¹² isindependently selected from —H, halogen, —(C₁-C₆) alkyl, —(C₃-C₆)cycloalkyl, 5-6 membered heterocyclyl, —OH, —O(C₁-C₆) alkyl,—O(CH₂)_(p)-(5-6 membered heterocyclyl), —O(CH₂)_(p)—O(C₁-C₆) alkyl,—NH₂, —CN, —NH(C₁-C₆) alkyl, —N(C₁-C₆ alkyl)₂, —NH(CH₂)_(p)—O(C₁-C₆)alkyl, —NH(CH₂)_(p)—N(C₁-C₆ alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl,and —C(═O)N(C₁-C₆ alkyl)₂; and p is an integer selected independentlyfrom 1, 2, 3, and
 4. 15. The method according to claim 14, wherein X is—O—.
 16. The method according to claim 14, wherein R⁵ is selected from—H, —(C₁-C₇) hydrocarbyl, and halogen.
 17. The method according to claim14, wherein one of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ is N, and the remainderof Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹².
 18. The method according toclaim 17, wherein one of Q² and Q⁶ is N; the other of Q² and Q⁶ isC—R¹²; and Q¹, Q³, Q⁴, Q⁵ and Q⁷ are C—R¹².
 19. The method according toclaim 14, wherein the compound according to Formula V(a) is selectedfrom:isoxazolidin-2-yl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;[4-(4-isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-isoxazolidin-2-yl-methanone;isoxazolidin-2-yl-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(4-chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-isoxazolidin-2-yl-methanone;{4-[4-(8-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-isoxazolidin-2-yl-methanone;isoxazolidin-2-yl-{4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-{4-[4-(7-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-[4-(4-quinoxalin-2-yl-phenoxy)-piperidin-1-yl]-methanone;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidmethoxyamide;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidmethoxymethylamide;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidethylamide;4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidmethylamide;4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidethylamide;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidhydroxyamide;N-ethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N,N-dimethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-methoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-ethoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-pyrrolidin-1-yl-methanone;N-methyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(1-piperidyl)methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-morpholinomethanone;N-methoxy-4-[4-(8-methoxy-7-quinolyl)phenoxy]piperidine-1-carboxamide;3-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-oxazolidin-2-one;1-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-pyrrolidin-2-one;N-ethyl-4-[4-(2-hydroxy-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-pyrrolidin-1-ylethyl)piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-morpholinoethyl)piperidine-1-carboxamide;(4-isopropylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;(4-methylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(4-morpholino-1-piperidyl)methanone;(4-ethylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;N-(cyclopropylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carb oxamide;N-(2-methoxyethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isobutoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carb oxamide;N-(2-dimethylaminoethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-[2-(1H-imidazol-4-yl)ethyl]-4-[4-(8-methyl-7-quinolyl)phenoxy]¬piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-tetrahydropyran-4-yl-piperidine-1-carboxamide;N-cyclobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbohydroxamic acid;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(oxazinan-2-yl)methanone;N-(cyclobutylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;azepan-1-yl-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide;N-ethyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;N-isobutyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-(cyclopropylmethyl)-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]-N-propoxypiperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carbohydroxamic acid;N-ethoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-ethoxy-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide;N-isobutyl-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carb oxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-methylsulfanyl-piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-ethylsulfanyl-piperidine-1-carboxamide,1-[4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carbonyl]pyrrolidin-2-one;or a pharmaceutically acceptable salt thereof.
 20. The method accordingto claim 14, wherein the compound of formula (Va) is

or a pharmaceutically acceptable salt thereof.
 21. The method accordingto claim 14, wherein the compound of formula (Va) is

or a pharmaceutically acceptable salt thereof.
 22. A method of treatinga subject who is suffering from weight gain associated with drug therapywith an antipsychotic agent, said method comprising administering to thesubject a therapeutically effective amount of a compound according toFormula V(a):

or a pharmaceutically acceptable salt thereof, wherein: R^(1b) isselected from —NR⁷R⁸ and —N(OR⁸)R⁷; R⁴ is selected from —H, —(C₁-C₆)alkyl, —OH, —O(C₁-C₆) alkyl, halogen, and —CN; X is selected from —O—and —S—; R⁵ is selected from —H, —C₁-C₇ hydrocarbyl, —C₃-C₆heterocyclyl; halogen, —(C₁-C₃) haloalkyl, —OR^(7a), —CN,—NR^(7a)R^(8a), —O(CH₂)_(n)NR^(7a)R^(8a), —O(CH₂)_(n)OR^(8a),—NR^(8a)(CH₂)_(n)NR^(7a)R^(8a), —NR^(8a)(CH₂)_(n)OR^(8a),—C(═O)NR^(7a)R^(8a), —C(═O)OR^(7a), 5-6 membered heteroaryl andsubstituted 5-6 membered heteroaryl; n is an integer selected from 1, 2,3, and 4; R⁷ is selected from —H, —(C₁-C₇) hydrocarbyl, substituted—(C₁-C₇) hydrocarbyl, —C(═O)R⁸, and —(C₁-C₆) heteroalkyl; R⁸ is selectedfrom —H, and —(C₁-C₆) alkyl, wherein R⁷ can optionally be structurallyconnected to R⁸ to form a 5 to 7 membered heterocyclyl ring; R^(7a) isselected from —H, —(C₁-C₇) hydrocarbyl, substituted —(C₁-C₇)hydrocarbyl, —C(═O)R⁸, and —(C₁-C₆) heteroalkyl; R^(8a) is selected from—H, and —(C₁-C₆) alkyl, wherein R^(7a) can optionally be structurallyconnected to R^(8a) to form a 5 to 7 membered heterocyclyl ring; Q¹, Q²,Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are independently selected from N and C—R¹²,provided that 1, 2 or 3 of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are N, and theremainder of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹²; each R¹² isindependently selected from —H, halogen, —(C₁-C₆) alkyl, —(C₃-C₆)cycloalkyl, 5-6 membered heterocyclyl, —OH, —O(C₁-C₆) alkyl,—O(CH₂)_(p)-(5-6 membered heterocyclyl), —O(CH₂)_(p)—O(C₁-C₆) alkyl,—NH₂, —CN, —NH(C₁-C₆) alkyl, —N(C₁-C₆ alkyl)₂, —NH(CH₂)_(p)—O(C₁-C₆)alkyl, —NH(CH₂)_(p)—N(C₁-C₆ alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆) alkyl,and —C(═O)N(C₁-C₆ alkyl)₂; and p is an integer selected independentlyfrom 1, 2, 3, and
 4. 23. The method according to claim 22, wherein X is—O—.
 24. The method according to claim 22, wherein R⁵ is selected from—H, —(C₁-C₇) hydrocarbyl, and halogen.
 25. The method according to claim22, wherein one of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ is N, and the remainderof Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ and Q⁷ are C—R¹².
 26. The method according toclaim 25, wherein one of Q² and Q⁶ is N; the other of Q² and Q⁶ isC—R¹²; and Q¹, Q³, Q⁴, Q⁵ and Q⁷ are C—R¹².
 27. The method according toclaim 22, wherein the compound according to Formula V(a) is selectedfrom:isoxazolidin-2-yl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;[4-(4-isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-isoxazolidin-2-yl-methanone;isoxazolidin-2-yl-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;{4-[4-(4-chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-isoxazolidin-2-yl-methanone;{4-[4-(8-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-isoxazolidin-2-yl-methanone;isoxazolidin-2-yl-{4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-{4-[4-(7-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;isoxazolidin-2-yl-[4-(4-quinoxalin-2-yl-phenoxy)-piperidin-1-yl]-methanone;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidmethoxyamide;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidmethoxymethylamide;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidethylamide;4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidmethylamide;4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acidethylamide;4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acidhydroxyamide;N-ethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N,N-dimethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-methoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-ethoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-pyrrolidin-1-yl-methanone;N-methyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(1-piperidyl)methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-morpholinomethanone;N-methoxy-4-[4-(8-methoxy-7-quinolyl)phenoxy]piperidine-1-carboxamide;3-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-oxazolidin-2-one;1-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-pyrrolidin-2-one;N-ethyl-4-[4-(2-hydroxy-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-pyrrolidin-1-ylethyl)piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-morpholinoethyl)piperidine-1-carboxamide;(4-isopropylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;(4-methylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(4-morpholino-1-piperidyl)methanone;(4-ethylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;N-(cyclopropylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carb oxamide;N-(2-methoxyethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-isobutoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carb oxamide;N-(2-dimethylaminoethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;N-[2-(1H-imidazol-4-yl)ethyl]-4-[4-(8-methyl-7-quinolyl)phenoxy]¬piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-tetrahydropyran-4-yl-piperidine-1-carboxamide;N-cyclobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbohydroxamic acid;[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(oxazinan-2-yl)methanone;N-(cyclobutylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;azepan-1-yl-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;4-[4-(8-methyl-7-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide;N-ethyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;N-isobutyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-(cyclopropylmethyl)-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]-N-propoxypiperidine-1-carboxamide;4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carbohydroxamic acid;N-ethoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;N-ethoxy-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;N-isopropoxy-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide;N-isobutyl-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carb oxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-methylsulfanyl-piperidine-1-carboxamide;4-[4-(4-methyl-3-quinolyl)phenoxy]-N-ethylsulfanyl-piperidine-1-carboxamide,1-[4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carbonyl]pyrrolidin-2-one;or a pharmaceutically acceptable salt thereof.
 28. The method accordingto claim 22, wherein the compound of formula (Va) is

or a pharmaceutically acceptable salt thereof.
 29. The method accordingto claim 22, wherein the compound of formula (Va) is

or a pharmaceutically acceptable salt thereof.
 30. The method of claim22, wherein the antipsychotic agent is selected from clozapine,risperidone, aripiprazole, olanzapine, quetiapine and ziprasidone andcombinations thereof.